Bruton&#39;s tyrosine kinase inhibitors

ABSTRACT

Bruton&#39;s tyrosine kinase (Btk) inhibitors have the following Formula (I):

The present application is a continuation-in-part application of U.S.Ser. No. 16/070,520, filed on Jul. 16, 2018, which is a national stageapplication of PCT/US2017/013815, filed on Jan. 17, 2017, which claimspriority to U.S. provisional application No. 62/281,252, filed on Jan.21, 2016, which is incorporated by reference for all purposes as iffully set forth herein.

FIELD OF THE INVENTION

Described herein are Bruton's tyrosine kinase inhibitors, methods ofmaking such inhibitors, and pharmaceutical compositions containing suchinhibitors.

BACKGROUND OF THE INVENTION

Bruton's tyrosine kinase (Btk) plays an important role in signaltransduction in B cells and is a factor that contributes to thesurvival, differentiation, proliferation, and activation of B cells.There is currently a need for methods of treating diseases in which Bcells or mast cells participate. Btk is also known to participate inmast cell activation and in the physiological functions of platelets.Therefore, Btk inhibitors are effective for the treatment of diseases inwhich B cells or mast cells participate, for example, allergic diseases,autoimmune diseases, inflammatory diseases, thromboembolic diseases, andcancers.

SUMMARY OF THE INVENTION

The Btk inhibitors described herein having the following structure:Formula (I):

In Formula (I), A is N or CH; B, C, and D are each N or C—R¹, with theproviso that only one or two of A, B, C, and D can be N; R¹ is hydrogen,halogen, OH, CN, C₁₋₆alkyl, C₁₋₄alkoxy, C₁₋₆alkyl substituted with oneto five fluorines, C₁₋₄alkoxy substituted with one to five fluorines,C₁₋₄alkoxy substituted with OH, C₁₋₄alkoxy substituted with NH₂ orN(CH₃)₂, or

R² is

—X-E is one of the followings: (1) X is O, OCR^(a)R^(b), CR^(a)R^(b)O,S(O), S(O)₂, CR^(a)R^(b), NR^(c)(C═O), C═ONR^(c) or a bond; and E is ahydrogen, an aryl or a heteroaryl substituted with one to three R⁵substituents; or a 3-7 membered saturated or partially unsaturatedcarbocyclic ring, an 8-10 membered bicyclic saturated, partiallyunsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur, a 4-7 membered saturated or partially unsaturated heterocyclicring having 1-3 heteroatoms independently selected from nitrogen,oxygen, or sulfur, a 7-10 membered bicyclic saturated or partiallyunsaturated heterocyclic ring having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclicheteroaryl ring having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; or (2) —X-E is hydrogen, halogen, —OR^(a),—O(CH₂)₁₋₄R^(a), —CN, —NO₂; R⁴ and R⁵ are each independently selectedfrom the group consisting of hydrogen, halogen, hydroxy, cyano, OCF₃,OCF₂H, C₁₋₆ alkyl, optionally substituted with one to five fluorines,C₃₋₆ cycloalkyl, optionally substituted with one to five fluorines,C₁₋₄alkoxy, optionally substituted with one to five fluorines, C₁₋₄alkylthio, optionally substituted with one to five fluorines, C₁₋₄alkylsulfonyl, optionally substituted with one to five fluorines,carboxy, C₁₋₄ alkyloxycarbonyl, and C₁₋₄ alkylcarbonyl; R^(a) and R^(b)are each independently hydrogen, fluorine, or C₁₋₃ alkyl, optionallysubstituted with one to five fluorines; R^(c) is hydrogen or C₁₋₃ alkyl,optionally substituted with one to five fluorines; R³ is a group havinga double bond, an isomer thereof, a tautomer thereof, a pharmaceuticalacceptable solvate thereof, or a pharmaceutical acceptable prodrugthereof. In formula (I), “B” does not represent Boron; “C” does notpresent Carbon; and “D” does not represent Deuterium.

In another embodiment, E is selected from aryl, heteroaryl, carbocyclyl,heterocyclyl, any of which is optionally substituted with one to threeR⁵ substituents.

In another embodiment, R³ is selected from the group consisting of:

Y is C(═O), OC(═O), NHC(═O), S═O, S(═O)₂, or NHS(═O)₂; and R⁶, R⁷, R⁸are each independently hydrogen, halogen, CN, C₁₋₄ alkyl, C₁₋₆alkoxyalkyl, C₁₋₈ alkylaminoalkyl, or C₁₋₄ alkylphenyl; or R⁷ and R⁸taken together form a bond.

In another embodiment, R³ is selected from the group consisting of

Y is C(═O), OC(═O), NHC(═O), S═O, S(═O)₂, or NHS(═O)₂; R⁶, R⁷, R⁸ areeach independently hydrogen, halogen, CN, C₁₋₄ alkyl, C₁₋₆ alkoxyalkyl,C₁₋₈ alkylaminoalkyl, or C₁₋₄ alkylphenyl; and R⁷ and R⁸ are optionallytaken together form a bond.

In another embodiment, R³ is selected from the group consisting of:

In another embodiment, A is CH, B is N; C is CH; D is C—R¹; and R¹ ishydrogen, halogen, OH, CN, C₁₋₆alkyl, C₁₋₄alkoxy, C₁₋₆alkyl substitutedwith one to five fluorines, C₁₋₄alkoxy substituted with one to fivefluorines, C₁₋₄alkoxy substituted with OH, C₁₋₄alkoxy substituted withNH₂ or N(CH₃)₂, or

In another embodiment, R¹ is hydrogen, hydrogen, Cl, F, OH, CN, —CHF₂,—CH₃, —OCH₃—OCH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH(CH₃)₂, —OCH₂CH₂OH,—OCH₂CH₂NH₂, —OCH₂CH₂N(CH₃)₂, or

In another embodiment, the compound is selected from the groupconsisting of

In another embodiment, a pharmaceutical composition includes atherapeutically effective amount of the compound of Formula (I), and apharmaceutically acceptable excipient.

In another embodiment, a method for treating an autoimmune diseaseincludes administering to a subject in need thereof a compositioncontaining a therapeutically effective amount of the compound of Formula(I).

In another embodiment, a pharmaceutical composition for preventing ortreating cancers, tumors, inflammatory diseases, autoimmune diseases, orimmunologically mediated disease includes a therapeutically effectiveamount of the compound of Formula (I), and a pharmaceutically acceptableexcipient.

In another embodiment, a method for treating an autoimmune disease,cancers, tumors, inflammatory diseases, or immunologically mediateddiseases includes administering to a subject in need thereof acomposition containing a therapeutically effective amount of thecompound of Formula (I) and other therapeutic agents.

DETAILED DESCRIPTION OF THE INVENTION

The methods described herein include administering to a subject in needa composition containing a therapeutically effective amount of one ormore Btk inhibitor compounds described herein.

Prodrugs means any compound which releases an active parent drugaccording to Formula I in vivo when such prodrug is administered to amammalian subject. Prodrugs of a compound of Formula I are prepared bymodifying functional groups present in the compound of Formula I in sucha way that the modifications may be cleaved in vivo to release theparent compound. Prodrugs may be prepared by modifying functional groupspresent in the compounds in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompounds.

Tautomers mean compounds produced by the phenomenon wherein a proton ofone atom of a molecule shifts to another atom. Tautomers also refer toone of two or more structural isomers that exist in equilibrium and arereadily converted from one isomeric form to another. One of ordinaryskill in the art would recognize that other tautomeric ring atomarrangements are possible. All such isomeric forms of these compoundsare expressly included in the present disclosure.

Isomers mean compounds having identical molecular formulae but differ inthe nature or sequence of bonding of their atoms or in the arrangementof their atoms in space. Isomers that differ in the arrangement of theiratoms in space are termed stereoisomers. Stereoisomers that are notmirror images of one another are termed diastereomers, and those thatare non-superimposable mirror images of each other are termedenantiomers. When a compound has an asymmetric center, for example, itis bonded to four different groups, a pair of enantiomers is possible. Achiral compound can exist as either individual enantiomer or as amixture thereof. Unless otherwise indicated, the description is intendedto include individual stereoisomers as well as mixtures.

Certain compounds of the present disclosure can exist in unsolvatedforms as well as solvated forms, including hydrated forms. Solvatesrefer to a complex formed by combination of solvent molecules with thecompound of Formula I. The solvent can be an organic compound, aninorganic compound, or a mixture thereof.

Pharmaceutically acceptable salts represent those salts which are,within the scope of medical judgement, suitable for use in contact forthe tissues of humans and lower animals without undue toxicity,irritation, allergic response and the like, and are commensurate with areasonable benefit/risk ratio. They may be obtained during the finalisolation and purification of the compounds of the invention, orseparately by reacting the free base function with a suitable mineralacid such as hydrochloric acid, phosphoric acid, or sulfuric acid, orwith an organic acid such as for example ascorbic acid, citric acid,tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid,glycolic acid, succinic acid, propionic acid, acetic acid,methanesulfonic acid, and the like. The acid function can be reactedwith an organic or a mineral base, like sodium hydroxide, potassiumhydroxide or lithium hydroxide.

Therapeutically effective amount means an amount of compound or acomposition of the present invention effective in inhibiting Bruton'styrosine kinase and thus producing the desired therapeutic effect.

As used herein, the term alkyl refers to a monovalent straight orbranched chain, saturated aliphatic hydrocarbon radical having a numberof carbon atoms in the specified range. For example, C₁₋₆ alkyl refersto any of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-,sec- and t-butyl, n- and iso-propyl, ethyl and methyl. Alkyl alsoincludes saturated aliphatic hydrocarbon radicals wherein one or morehydrogens are replaced with deuterium, for example, CD₃.

The term branched alkyl refers to an alkyl group as defined above exceptthat straight chain alkyl groups in the specified range are excluded. Asdefined herein, branched alkyl includes alkyl groups in which the alkylis attached to the rest of the compound via a secondary or tertiarycarbon. For example, isopropyl is a branched alkyl group.

The term cycloalkyl refers to any monocyclic ring of an alkane having anumber of carbon atoms in the specified range. For example,C₃₋₆cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

The term halogen refers to fluorine, chlorine, bromine and iodine(alternatively referred to as fluoro, chloro, bromo, and iodo).

The term haloalkyl refers to an alkyl group as defined above in whichone or more of the hydrogen atoms have been replaced with a halogen(i.e., F, Cl, Br and/or I). For example, C₁₋₆ haloalkyl refers to a C₁to C₆ linear or branched alkyl group as defined above with one or morehalogen substituents. The term fluoroalkyl has an analogous meaningexcept that the halogen substituents are restricted to fluoro. Suitablefluoroalkyls include the series (CH₂)₀₋₄ CF₃.

The term C(O) or CO refers to carbonyl. The terms S(O)₂ or SO₂ refers tosulfonyl. The term S(O) or SO refers to sulfinyl.

The term aryl refers to phenyl, naphthyl, tetrahydronaphthyl, idenyl,dihydroindenyl and the like. An aryl of particular interest is phenyl.

The term heteroaryl refers to (i) a 5- or 6-membered heteroaromatic ringcontaining from 1 to 4 heteroatoms independently selected from N, O andS, or (ii) is a heterobicyclic ring selected from quinolinyl,isoquinolinyl, and quinoxalinyl. Suitable 5- and 6-memberedheteroaromatic rings include, for example, pyridyl (also referred to aspyridinyl), pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl,thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isooxazolyl, oxadiazolyl, oxatriazolyl, thiazolyl,isothiazolyl, and thiadiazolyl. A class of heteroaryls of interestconsists of (i) 5- and 6-membered heteroaromatic rings containing from 1to 3 heteroatoms independently selected from N, O and S, and (ii)heterobicyclic rings selected from quinolinyl, isoquinolinyl, andquinoxalinyl. Heteroaryls of particular interest are pyrrolyl,imidazolyl, pyridyl, pyrazinyl, quinolinyl (or quinolyl), isoquinolinyl(or isoquinolyl), and quinoxalinyl.

Examples of 4- to 7-membered, saturated heterocyclic rings within thescope of this invention include, for example, azetidinyl, piperidinyl,morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl,oxazolidinyl, isoxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl,tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl,hexahydropyrimidinyl, thiazinanyl, thiazepanyl, azepanyl, diazepanyl,tetrahydropyranyl, tetrahydrothiopyranyl, and dioxanyl. Examples of 4-to 7-membered, unsaturated heterocyclic rings within the scope of thisinvention include mono-unsaturated heterocyclic rings corresponding tothe saturated heterocyclic rings listed in the preceding sentence inwhich a single bond is replaced with a double bond (e.g., acarbon-carbon single bond is replaced with a carbon-carbon double bond).

It is understood that the specific rings listed above are not alimitation on the rings which can be used in the present invention.These rings are merely representative.

Synthetic methods for preparing the compounds of the present inventionare illustrated in the following Schemes, Methods, and Examples.Starting materials are commercially available or may be preparedaccording to procedures known in the art or as described herein. Thecompounds of the invention are illustrated by means of the specificexamples shown below. However, these specific examples are not to beconstrued as forming the only genus that is considered as the invention.These examples further illustrate details for the preparation of thecompounds of the present invention. Those skilled in the art willreadily appreciate that known variations in the conditions and processescan be used to prepare such compounds.

The Btk inhibitor compounds of Formula I can be prepared by methods wellknown in the art of organic chemistry. The starting material used forthe synthesis of these compounds can be either synthesized or obtainedfrom commercial sources, such as, but not limited to, China chemicalcompanies or Sigma-Aldrich Chemical Co. (St. Louis, Mo.) at China. Thecompounds described herein, and other related compounds having differentsubstituents are optionally synthesized using techniques and materials,such as described, for example, in March, ADVANCED ORGANIC CHEMISTRY 4thEd., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4thEd., Vols. A and B (Plenum 2000, 2001); Fieser and Fieser's Reagents forOrganic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd'sChemistry of Carbon Compounds, Volumes 1-5 and Supplementals (ElsevierScience Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wileyand Sons, 1991); and Larock's Comprehensive Organic Transformations (VCHPublishers Inc., 1989). Other methods for the synthesis of compoundsdescribed herein may be found in United States Patent ApplicationPublication No. US 2011/0130429 A1, Burgey et al. Bioorganic& MedicinalChemisty Letters 10 (2006) 5052-5056. The definitions of chemistry termsused in this application may be found in these reference (if nototherwise defined herein). As a guide the following synthetic methodsmay be utilized.

During the synthetic sequences it may be necessary and/or desirable toprotect sensitive or reactive groups on any of the molecules concerned.This is achieved by means of conventional protecting groups, such asthose described in T. W Greene and P. G. M. Wutts “Protective groups inOrganic Synthesis” 3rd Edition, John Wiley and Sons, 1999. Theprotective groups are optionally removed at a convenient subsequentstage using methods well known in the art. The products of the reactionsare optionally isolated and purified. If desired, using conventionaltechniques, but not limited to, filtration, distillationcrystallization, chromatography and the like. Such materials areoptionally characterized using conventional means, including physicalconstant and spectra data.

Compounds described herein may possess one or more sterocenters and eachcenter may exist in the R or S configuration. The compounds presentedherein include all diasterometic, enantiomeric, and epimeric forms aswell as the appropriate mixtures thereof.

The Btk inhibitor compounds of Formula I can be, for example,1H-pyrazolo[4,3-c]pyridine derivatives. Specifically, the Btk inhibitorcompounds of Formula I can be, for example, compounds F, wherein R₁-R₂have the previously defined meanings. A non-limiting example of asynthetic approach towards the preparation of compounds F can beprepared by the general synthetic route shown in Scheme I and Scheme II.

Referring to Scheme I, different aldehyde (B), in which FG is afunctional group (e.g. ester, protected anilines, protected phenols,bromide), could be added to a range of substituted o-haloaromatics A toform an alcohol, followed by oxidation of the product C with CrO₃ inacetone to give benzoyl D. Ring closure D with (NH₂)₂—H₂O under refluxto obtain the key intermediates indazole E. Intermediate E is coupledwith R₂OH via Mitsunobu reaction or with R₂OTs via replacement to givethe intermediate G, which then are derivatived by metal catalystcoupling reaction using appropriately substituted phenylboronic acid(corresponding boronic esters may also be used) directly affords thedesired compounds F. In a typical procedure, a mixture of intermediatesG, a copper catalyst (e.g. Cu(OAc)₂), base (e.g. TEA, DIPEA or the like)and an aryl boronic acid or aryl boronic ester in a suitable solventsuch as DCM, or toluene to form compounds F (FG is converted to groupsdefined for XAr).

Referring to Scheme II, compounds F can be obtained from another route,selective ortho-lithiation in dry THF with LDA in suitu made and laterreaction with DMF to afford aldehyde H, which reacts with (NH₂)₂—H₂Ounder reflux to obtain the key intermediates indazole I, thenregioselective bromination or iodation with Br₂/I₂ or NBS/NIS to affordcompound J. Coupling reaction of the 1-nitrogen on the indazole withR₂OH via Mitsunobu reaction or with R₂OTs via replacement to give theintermediate K, which then are derivatived by metal catalyst couplingreaction using appropriately substituted phenylboronic acid(corresponding boronic esters may also be used) affords a keyintermediate G or directly affords the desired compounds F. Thetransformation from G to F is synthesized in a similar manner as beforeshowed at Scheme I.

Alternatively, compound F can be obtained from compounds G, in which FGis a functional group (e.g. ester, protected anilines, protectedphenols, bromide) that can be easily converted to groups defined forXAr. Non-limiting examples of suitable functional groups in compounds Gare a benzyl ether, dibenzyl anime, or methyl ester, which can betreated with base or Pd/C/H₂ to form the key intermediates G-1a, G-2a,G-3a, then form corresponding compounds F-1, F-2, F-3, F-4 at SchemeIII.

The deprotection reactions for the protective groups of compound F inScheme IV are known and can be run by the methods described below.Examples here are (a) deprotection reaction under acidic conditions forBoc protecting group and (b) deprotection reactions based onhydrogenolysis for benzyl protecting group. After deprotection withthese conditions, coupling with, but not limited to, an acid chloride,such as, but not limited to, aryloyl chloride, completes the synthesisto provide compound F-b.

General experimental conditions: Preparative thin layer chromatography(PTLC) was performed on 20×20 cm plates (500 micron thick silica gel).Silica gel chromatography was performed on a Biotage Horizon flashchromatography system. 1H NMR spectra were recorded on a Bruker AscendTM 400 spectrometer at 400 MHz at 298° K, and the chemical shifts aregiven in parts per million (ppm) referenced to the residual protonsignal of the deuterated solvents: CDCl₃ at δ=7.26 ppm and CH₃OH orCH₃OD at 6=3.30 ppm. LCMS spectra were taken on an Agilent Technologies1260 Infinity or 6120 Quadrupole spectrometer. The mobile phase for theLC was acetontrile (A) and water (B) with 0.01% formic acid, and theeluent gradient was from 5-95% A in 6.0 min, 60-95% A in 5.0 min,80-100% A in 5.0 min and 85-100% A in 10 min using a SBC18 50 mm×4.6mm×2.7 m capillary column. Mass spectra (MS) were measured byelectrospray ion-mass spectroscopy (ESI). All temperatures are indegrees Celsius unless otherwise noted.

Analytical HPLC mass spectrometry conditions:

LC1: Column: SB-C18 50 mm×4.6 mm×2.7 μm

Temperature: 50° C.

Eluent: 5:95 v/v acetonitrile/water+0.01% formic acid in 6 min.

Flow Rate: 1.5 mL/min, Injection 5 μL

Detection: PDA, 200-600 nm

MS: mass range 150-750 amu; positive ion electrospray ionization

LC2: Column: SB-C18 50 mm×4.6 mm×2.7 μm

Temperature: 50° C.

Eluent: 5:95 to 95:5 v/v acetonitrile/water+0.05% TFA over 3.00 min.

Flow Rate: 1.5 mL/min, Injection 5 μL

Detection: PDA, 200-600 nm

MS: mass range 150-750 amu; positive ion electrospray ionization

LC3: Column: SB-C18 50 mm×4.6 mm×2.7 μm

Temperature: 50° C.

Eluent: 10:90 to 98:2 v/v acetonitrile/water+0.05% TFA over 3.75 min.

Flow Rate: 1.0 mL/min, Injection 10 μL

Detection: PDA, 200-600 nm

MS: mass range 150-750 amu; positive ion electrospray ionization

List of Abbreviations

AcOH=acetic acid; Alk=alkyl; Ar=aryl; Boc=tert-butyloxycarbonyl;bs=broad singlet; CH₂Cl₂=dichloromethane; d=doublet; dd=doublet ofdoublets; DBU=1,8-diazabicyclo[5.4.0]undec-7-ene; DCM=dichloromethane;DEAD=diethyl azodicarboxylate; DMF=N,N-dimethylformamide; DMSO=dimethylsulfoxide; EA=ethyl acetate; ESI=electrospray ionization; Et=ethyl;EtOAc=ethyl acetate; EtOH=ethyl alcohol; h=hours; HOAc=acetic acid;LiOH=lithium hydroxide; m=multiplet; Me=methyl; MeCN=acetonitrile;MeOH=methyl alcohol; MgSO₄=magnesium sulfate; min=minutes; MS=massspectroscopy; NaCl=sodium chloride; NaOH=sodium hydroxide; Na₂SO₄=sodiumsulfate; NMR=nuclear magnetic resonance spectroscopy; PE=petroleumether; PG=protecting group; Ph=phenyl; rt=room temperature; s=singlet;t=triplet; TFA=trifluoroacetic acid; THF=tetrahydrofuran;Ts=p-toluenesulfonyl (tosyl).

The compounds of the present invention can be prepared following generalmethods detailed below. In certain embodiments, provided herein aremethods of making the tyrosine kinase inhibitor compounds describedherein. In certain embodiments, compounds described herein aresynthesized using the following synthetic schemes. In other embodiments,compounds are synthesized using methodologies analogous to thosedescribed below by the use of appropriate alternative startingmaterials. All key intermediates were prepared according to thefollowing methods.

Intermediate 1: (4-(2-chloro-3-methoxyphenoxy) phenyl) boronic acid

Step A: 2-chloro-3-hydroxybenzaldehyde (1)

To a suspension of 3-hydroxybenzaldehyde (5 g, 40.98 mmol) in AcOH (10mL) was added carefully t-BuOCl (5 mL, 45.08 mmol) with stirring. It wasallowed to cool and stirred for 16 hours, resulting in a whiteprecipitate. The solid was filtered, washed with H₂O and dried to givethe title product (3 g, 46.9%). ¹H-NMR (400 MHz, CDCl₃): δ 10.66 (br,1H), 10.33 (s, 1H), 7.31-7.25 (m, 3H).

Step B: 2-chloro-3-hydroxybenzaldehyde (2)

To a solution of 2-chloro-3-hydroxybenzaldehyde 1 (3.4 g, 21.66 mmol) inDMF (22 mL) was added K₂CO₃ (3.59 g, 26 mmol) followed by MeI (2 mL,32.5 mmol), and the mixture was stirred at room temperature for 18hours. Following concentration in vacuum, the residue was taken up inethyl acetate, washed with H₂O, brine, dried over Na₂SO₄, andconcentrated. Purification by column chromatography on silica gel withethyl acetate/hexanes 1/5 afforded the title product (3.5 g, 95.1%).¹H-NMR (400 MHz, CDCl₃): δ 10.53 (s, 1H), 7.53 (d, J=7.6 Hz, 1H),7.36-7.32 (m, 1H), 7.01 (d, J=8.8 Hz, 1H), 3.95 (s, 3H).

Step C: 2-chloro-3-hydroxybenzaldehyde (3)

To a solution of 2-Chloro-3-Methoxybenzaldehyde 2 (2 g, 11.7 mmol) inDCM (50 ml) was added 3-Chloroperoxybenzoic acid (3 g, 17.5 mmol). Themixture was stirred for 12 hours at 40° C. Filtered, the residue wascontracted to a soled. The soled was desalted in 18 mL of MeOH, then 5mL of 10% NaOH was added with cooling. After stirring for 45 min at 10°C., the mixture was condition at 30° C. on a rotary evaporator to removethe MeOH, then 22 mL of 5% NaOH, was added and the solution was addedwith Conc HCl with cooling, then extracted (3×20) with EA, wished withH₂O, 5% NaHCO₃, dried over Na₂SO₄ and concentrated in vacuo to affordthe title compound (1.2 g, 66.6%). ¹H-NMR (400 MHz, CDCl₃): δ 7.14-7.10(m, 1H), 6.67 (d, J=8.4 Hz, 1H), 6.51 (d, J=8.4 Hz, 1H), 5.62 (s, 1H),3.89 (s, 3H).

Step D: 1-(4-bromophenoxy)-2-chloro-3-methoxybenzene (4)

To a solution of 1-bromo-4-iodobenzene (2.68 g, 9.5 mmol) in dioxene (40mL) was added 3 (1.5 g, 9.5 mmol), CuI (0.182 g, 0.95 mmol),N,N-Dimethylglycine hydrochloride (0.396 g, 2.85 mmol), Cs₂CO₃ (6.2 g,19 mmol). The mixture was stirred at 105° C. in N₂ for 18 h. The mixturewas Filtered, contracted and extracted with EA, The organic layer waswashed with water and brine, dried with anhydrous Na₂SO₄, and purifiedby flash chromatography to give the title product (1.2 g, 40.4%). ¹H-NMR(400 MHz, CDCl₃): δ 7.43-7.39 (m, 2H), 7.18-7.15 (m, 1H), 6.85-6.75 (m,3H), 6.65-6.15 (m, 1H), 3.93 (s, 3H).

Step E: 1-(4-bromophenoxy)-2-chloro-3-methoxybenzene (5)

To a solution of 4 (1.2 g, 3.85 mmol) in THF (30 mL) was cooled to −78°C. under N₂, n-BuLi (1.82 mL, 4.61 mmol), was added dropwise under sametemperature. The mixture was stirred for 30 min at same temperature.Triisopropyl borate (0.868 g, 4.61 mmol), was added dropwise under sametemperature. After 15 min, the mixture was allowed to room temperatureand stirred for 2 h, then 2 N HCl was added to adjust to pH=5 andstirred for 30 min, then the mixture was The mixture was extracted withEA, The organic layer was washed with water and brine, dried withanhydrous Na₂SO₄, give the title crude product (0.4 g crude).

Example 1:(R)-1-(3-(3-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one

Step A: (4-(benzyloxy)phenyl)(4-chloropyridin-3-yl)methanol(2)

To a solution of diisopropylamine (4.1 mL, 29.8 mmol) in dry THF (64 mL)at −78° C. was added a 2.5M BuLi solution in hexane (15 mL, 29.8 mmol).The mixture was allowed to warm to 0° C. and stirred about 1 h, then thesolution was cooled to −78° C. and 4-chloropyridine (3.07 g, 27.1 mmol)in 10 mL of dry THF was added. The reaction mixture was stirred foradditional 4 h, and then the corresponding 4-(benzyloxy)benzaldehyde(5.75 g, 27.1 mmol) was added and the mixture was stirred and allowed towarm to room temperature overnight. The reaction was quenched with H₂O(25 mL), and the mixture was extracted with Et₂O (3×50 mL). The organicphases were combined, dried over Na₂SO₄, Volatile components wereremoved under vacuum and the residue was purified by columnchromatography on silica gel (gradient: DCM/MeOH=200:1-50/1) to give thetitle product (2.5 g, yield 28.46%). ¹H-NMR (400 MHz, CDCl₃): δ 8.86 (s,1H), 8.36 (d, J=4.0 Hz, 1H), 7.39-7.23 (m, 8H), 6.94 (d, J=8.0 Hz, 2H),6.12 (s, 1H), 5.03 (s, 2H), 2.98 (s, 1H), 2.16 (s, 1H). LCMS: m/z=326,328 [M+H]⁺.

Step B: (4-(benzyloxy) phenyl)(4-chloropyridin-3-yl)methanone (3)

A solution of (4-(benzyloxy)phenyl)(4-chloropyridin-3-yl)nethanol (2) (1g, 3.07 mmol) in dry acetone (10 mL) was cooled to 0° C. and CrO₃ (0.92g, 9.23 mmol) was added carefully in small portions. The resultingsolution was stirred at room temperature until complete consumption ofthe starting material (3 h), then reaction was quenched with 2-propanol(6 mL), and the mixture was stirred 30 min. A saturated solution ofNaHCO₃ (50 mL) was finally added to precipitate the chromium salts thatwere filtered over celite and washed with CH₂Cl₂ (6×15 mL). The solventwere removed under vacuum and the residue was purified by columnchromatography on silica gel (gradient: DCM/MeOH=200:1), to give thetitle product (0.7 g, yield 70.7%). ¹H-NMR (400 MHz, CDCl₃): δ 8.61 (d,J=8.0 Hz, 1H), 8.58 (S, 1H), 7.79 (d, J=8.0 Hz, 2H), 7.44-7.35 (m, 6H),7.04 (d, J=8.0 Hz, 2H), 5.15 (s, 2H). LCMS: m/z=324, 326 [M+H]⁺.

Step C: 3-(4-(benzyloxy)phenyl)-1H-pyrazolo[4,3-c]pyridine (4)

To a stirred solution(4-(benzyloxy)phenyl)(4-chloropyridin-3-yl)methanone (3) (0.7 g, 2.16mol) in absolute ethanol (5 ml) was added hydrazine (1.08 g, 17.3 mol).The solution was heated under reflux for 3 h, then cooled and theproduct filtered off and washed consecutively with water and methanol togive the title product (0.54 g, yield 83%). ¹H-NMR (400 MHz, DMSO-d6):δ13.48 (br, 1H), 9.39 (s, 1H), 8.37 (d, J=8.0 Hz, 1H), 8.01 (d, J=8.0Hz, 2H), 7.56-7.35 (m, 6H), 7.18 (d, J=8.0 Hz, 2H), 5.20 (S, 2H). LCMS:m/z=302 [M+H]⁺.

Step D:(R)-tert-butyl-3-(3-(4-(benzyloxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate(5)

Into a 100 mL 3-necked round-bottom flask, was placed a solution of3-(4-(benzyloxy)phenyl)-1H-pyrazolo[4,3-c]pyridine (4) (0.5 g, 1.66mmol) in N,N-dimethylformamide (41 mL),(S)-tert-butyl-3-(tosyloxy)pyrrolidine-1-carboxylate (0.68 g, 1.99mmol), and Cs₂CO₃ (0.97 g, 2.98 mmol). The resulting solution wasstirred for 12 h at 600° C. and then quenched by the addition of 100 mLof water. The resulting solution was extracted with EA and the organiclayers combined. The organics were washed with brine, dried overanhydrous NaHCO₃, The solvent were removed under vacuum and the residuewas purified by column chromatography on silica gel (gradient:DCM/MeOH=200:1-100:1) to give the title product (0.7 g, yield 89.7%).¹H-NMR (400 MHz, CDCl₃): δ 9.32 (br, 1H), 8.45 (br, 1H), 7.85-7.83 (m,2H), 7.37-7.36 (m, 1H), 7.04-7.02 (m, 2H), 5.18-5.15 (m, 1H), 3.96-3.79(m, 3H), 3.63-3.59 (m, 1H), 2.89 (br, 1H), 2.45 (br, 1H), 1.47 (s, 9H).LCMS: m/z=471 [M+H]⁺.

Step E:(R)-tert-butyl-3-(3-(4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate(6)

A suspension of (R)-tert-butyl3-(3-(4-(benzyloxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate(5) (0.7 g, 1.48 mmol) and 10% Pd/C (0.1 g) in MeOH (15 mL) washydrogenated at 50 psi H₂ for 3 h. The suspension was filtered throughCelite and concentrated. The residue was dried in vacuo to give thetitle product (0.48 g, yield 85.7%). LCMS: m/z=381[M+H]⁺.

Step F: (R)-tert-butyl3-(3-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-pyrrolidine-1-carboxylate(7)

(R)-tert-butyl-3-(3-(4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate(6) (50 mg, 0.1 mmol), phenylboronic acid (25.4 mg, 0.2 mmol), TEA (21mg, 0.2 mmol) and 4 A molecular sieves (0.1 g) were added to DCM (10 mL)in a vial Copper (II) acetate (18.8 mg, 0.1 mmol) was added in oneportion. The mixture was stirred for about 22 h at room temperature,Volatile components were removed under vacuum, before being poured intoH₂O. The reaction mixture was extracted with EA, organic phase waspurified by column chromatography on silica gel (gradient:DCM/MeOH===100/1-50/1) to give the title product (40 mg, yield 88.8%).LCMS: m/z=457 [M+H]⁺.

Step G:(R)-1-(3-(3-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one(8)

(R)-tert-butyl3-(3-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-pyrrolidine-1-carboxylate(7) (40 mg, 0.087 mmol) were added to CF₃COOH/DCM=4/1 (5 mL) in oneportion. The mixture was stirred for about 1 h at it Volatile componentswere removed under vacuum to give the title product of crude product (30mg), and directly used in next step without further purification. LCMS:m/z=357 [M+H]⁺.

To a solution of Acryloyl chloride (8.7 mg, 0.095 mmol) in DCM (1 mL)was added to a stirred solution of(R)-3-(4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1H-pyrazolo[4,3-c]pyridine(8) (30 mg, 0.087 mmol) and TEA (44 mg, 0.43 mmol) in DCM (5 mL) at 0°C. The reaction mixture was stirred for 1 h, poured onto brine andextracted with DCM. The organic layer was dried, concentrated andrecrystallized from DCM/MeOH=100/1 to give the title product (16 mg,yield 45.7%). ¹H-NMR (400 MHz, CDCl₃): δ 9.35 (br, 1H), 8.49 (br, 1H),7.95-7.91 (m, 2H), 7.40-7.36 (m, 3H), 7.15-7.08 (m, 5H), 6.53-6.42 (m,2H), 5.76-5.71 (m, 1H), 5.27-5.15 (m, 1H), 4.17-4.03 (m, 3H), 3.85-3.82(m, 1H), 2.79-2.49 (m, 2H). LCMS: m/z=411.2 [M+H]⁺.

Example 2:(R)-1-(3-(3-(4-(2-chloro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en-1-one

Step A: 1H-pyrazolo[4,3-c]pyridine (2)

To a stirred solution 1H-pyrazolo[4,3-c]pyridine(1) (17 g, 0.12 mol) inabsolute ethanol (120 ml) was added hydrazine (80%) (75 g, 1.2 mol). Thesolution was heated under reflux for 5 h, EtOH was removed under vacuum,and the mixture was extracted with EA (10×100 mL), The organic phaseswere combined, dried over Na₂SO₄. Volatile components were removed undervacuum and the residue was purified by column chromatography on silicagel (gradient: DCM/MeOH=200:1-50/1) to give the title product (8 g,yield 57 1%). ¹H-NMR (400 MHz, CDCl₃): δ13.48 (br, 1H), 9.18 (s, 1H),8.44 (d, J=6.0 Hz, 1H), 8.25 (s, 1H), 7.45 (d, J=6.0 Hz, 1H). LCMS:m/z=120 [M+H]⁺.

Step B: 3-bromo-1H-pyrazolo[4,3-c]pyridine (3)

To a solution of 1H-pyrazolo[4,3-c]pyridine(2) (8 g, 67.2 mmol) in AcOH(100.0 mL), was added bromine (5.1 mL, 0.1 mol) at room temperature. Thereaction was stirred at room temperature for 72 h and quenched with 10%NaOH (aq.) to pH 12. The organics were separated. The aqueous layer wasextracted again with EA (10×100 mL). The organic phases were combined,dried over Na₂SO₄, volatile components were removed under vacuum and theresidue was purified by column chromatography on silica gel (gradient:DCM/MeOH=200:1-50/1) to give the title product (4.5 g, yield 34.3%).¹H-NMR (400 MHz, CDCl₃): δ13.32 (br, 1H), 9.06 (s, 1H), 8.54 (d, J=5.6Hz, 1H), 7.43 (d, J=5.6 Hz, 1H). LCMS: m/z=198, 200 [M+H]⁺

Step D:(R)-tert-butyl3-(3-bromo-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate(4)

Into a 100 mL round-bottom flask, was placed a solution of3-bromo-1H-pyrazolo[4,3-c]pyridine (3) (2 g, 10 mmol) in DMF (20 mL),(S)-tert-butyl 3-(tosyloxy)piperidine-1-carboxylate (4.3 g, 12 mmol),and Cs₂CO₃ (5.9 g, 18 mmol). The resulting solution was stirred for 24 hat 65° C. and then quenched by the addition of 100 mL of water. Theresulting solution was extracted with EA and the organic layerscombined. The organics were washed with brine, dried over anhydrousNaHCO₃, The solvent were removed under vacuum and the residue waspurified by column chromatography on silica gel (gradient:DCM/MeOH=200:1-100:1) to give the title product (0.8 g, yield 21.0%).¹H-NMR (400 MHz, CDCl₃): δ 8.97 (s, 1H), 8.48 (d, J=5.6 Hz, 1H), 7.36(d, J=5.6 Hz, 1H), 4.43-4.38 (m, 3H), 3.2 (br, 1H), 2.88-2.81 (m, 1H),2.30-2.17 (m, 2H), 1.95-1.91 (m, 1H), 1.72-1.62 (m, 1H), 1.46 (s, 9H).LCMS: m/z=382 [M+H]⁺.

Step E:(R)-tert-butyl-3-(3-(4-(2-chloro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate(5)

To a solution of 4 (100 mg, 0.262 mmol) and(4-(2-chloro-3-methoxyphenoxy) phenyl) boronic acid (109.9 mg, 0.393mmol) in toluene (5 mL) and water (1 mL) was added K₂CO₃ (72 mg, 0.524mmol) followed by (Ph₃P)₄Pd (30 mg) under N₂ with stirring. The mixturewas refluxed for 8 h until the material was disappeared. The reactionmixture was cooled to room temperature. The dioxane was removed byrotary evaporation. The residue was poured into water and extracted withEA. The organic layer was dried over Na₂SO₄, filtered and the solventwas removed under vacuum, the residue was purified by flashchromatography on silica gel using 100:1-50:1 DCM:MeOH, give the titleproduct (50 mg). LCMS: m/z=534.2 [M+H]⁺

Step F:(R)-1-(3-(3-(4-(2-chloro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en-1-one(6)

Intermediate 5 (50 mg, 0.093 mmol) were added to CF₃COOH/DCM=4/1 (5 mL)in one portion. The mixture was stirred for about 2 h at rt. Volatilecomponents were removed under vacuum to give the title crude product,and directly used in next step without further purification. A solutionof Acryloyl chloride (8.5 mg, 0.095 mmol) in DCM (1 mL) was added to astirred solution of crude residue, TEA (44 mg, 0.43 mmol) in DCM (5 mL)at 00° C. The reaction mixture was stirred for 1 h, poured into brineand extracted with DCM. The organic layer was dried, concentrated andrecrystallized from DCM/MeOH=100/1 to give the title product (29 mg,yield 65%). ¹H-NMR (400 MHz, CDCl₃): δ 9.35 (s, 1H), 8.45 (d, J=5.6 Hz,1H), 7.93 (d, J=8.4 Hz, 2H), 7.45-7.34 (m, 1H), 7.24-7.20 (m, 2H), 7.11(d, J=8.4 Hz, 2H), 6.80 (d, J=8.4 Hz, 1H), 6.73 (d, J=8.4 Hz, 2H),26.68-6.53 (m, 1H), 6.38-6.34 (m, 1H), 5.77-5.69 (m, 1H), 4.94-4.91 (m,0.5H), 4.72-4.48 (br, 1.4H), 4.25-4.07 (m, 1H), 3.96 (s, 3H),3.80-3.3.78 (m, 0.6H), 3.24-3.22 (m, 1H), 2.91 (br, 0.4H), 2.50-2.47 (m,1H), 2.30-2.28 (m, 1H), 2.06-2.02 (m, 1H), 1.73-1.71 (m, 1H). LCMS:m/z=489.2 [M+H]⁺.

Example 3:(R)-1-(3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one

Step A: 1-(4-bromophenoxy)-2-fluoro-3-methoxybenzene (1)

To a solution of 1-bromo-4-iodobenzene (20.7 g, 73 mmol, 1.0 eq) indioxene (180 mL) was added 2-fluoro-3-methoxyphenol (10.4 g, 73 mmol,1.0 eq), CuI (1.39 g, 7.3 mmol, 0.1 eq), N,N-Dimethylglycinehydrochloride (2.03 g, 14.6 mmol, 0.2 eq), Cs₂CO₃ (35.9 g, 109.5 mmol,1.5 eq). The mixture was stirred at 100° C. in N₂ for 15 h, then mixturewas Filtered, contracted and extracted with EA, the organic layer waswashed with water and brine, dried with anhydrous Na₂SO₄, concentratedand the residue was purified by silica gel column chromatography to givethe title product 1 (9.2 g, 42.4%). ¹H-NMR (400 MHz, CDCl₃): δ 7.59 (d,J=7.6 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.00-7.04 (m, 1H), 6.87 (d, J=8.0Hz, 1H), 6.74-6.81 (m, 2H), 6.62-6.66 (m, 1H), 3.92 (s, 3H).

Step B: (4-(2-fluoro-3-methoxyphenoxy)phenyl)boronic acid

To a solution of 1 (9.2 g, 30.96 mmol, 1.0 eq) in THF (100 mL) wascooled to −78° C. under N₂, n-BuLi (16.1 mL, 40.25 mmol, 1.3 eq), wasadded dropwise under same temperature. The mixture was stirred for 50min at same temperature. Triisopropyl borate (7.57 g, 40.25 mmol, 1.3eq), was added dropwise under same temperature. After 15 min, themixture was allowed to room temperature and stirred for 2 h, then 1 NHCl was added to adjust to pH=5.0 and stirred for 30 min, then themixture was extracted with EA, The organic layer was washed with waterand brine, dried with anhydrous Na₂SO₄, filtered and concentrated givethe title crude product 2 (7.8 g, 95.8%).

Step C: (R)-tert-butyl3-(3-bromo-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate (3)

Into a 100 mL round-bottom flask, was placed a solution of3-bromo-1H-pyrazolo[4,3-c]pyridine (2.45 g, 23.34 mmol, 1.0 eq) in DMF(40 mL), (S)-tert-butyl 3-(tosyloxy)piperidine-1-carboxylate (5.06 g,14.48 mmol, 1.2 eq), and Cs₂CO₃ (6.1 g, 18.55 mmol, 1.5 eq). Theresulting solution was stirred for 12 h at 65° C. and then quenched bythe addition of 100 mL of water. The resulting solution was extractedwith EA (80 mL*3) and the organic layers combined. The organics werewashed with brine, dried over anhydrous Na₂CO₃, The solvent were removedunder vacuum and the residue was purified by silica gel columnchromatography (DCM/MeOH=200:1-100:1) to give the title product (3.5 g,yield 76.9%). ¹H-NMR (400 MHz, CDCl₃): δ 8.98 (s, 1H), 8.50 (d, J=4.8Hz, 1H), 7.32 (d, J=5.6 Hz, 1H), 3.91 (s, 1H), 3.76-3.80 (m, 2H),3.53-3.59 (m, 1H), 2.59 (s, 1H), 2.38-2.44 (m, 1H), 1.48 (s, 9H). LCMS:m/z=367 [M+H]⁺.

Step D: (R)-tert-butyl3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate(4)

To a solution of 3 (430 mg, 1.17 mmol, 1.0 eq) and 2 (460 mg, 1.76 mmol,1.5 eq) in dioxane (20 mL) and water (3 mL) was added K₂CO₃ (324 mg,2.34 mmol, 2.0 eq) and (Ph₃P)₄Pd (30 mg) under N₂ with stirring. Themixture was refluxed for 6 h until the material was disappeared. Thereaction mixture was cooled to room temperature. The dioxane was removedby rotary evaporation. The residue was poured into water and extractedwith EA. The organic layer was dried over Na₂SO₄, filtered and thesolvent was removed by rotary evaporation. The residue was purified withflash silica gel chromatography (DCM:MeOH=100:1-50:1) to give the titleproduct (0.5 g, yield 84.4%). ¹H-NMR (400 MHz, CDCl₃): δ 9.33 (s, 1H),8.46 (d, J=5.2 Hz, 1H), 7.94 (d, J=8.4 Hz, 2H), 7.34 (d, J=5.6 Hz, 1H),7.14 (d, J=8.8 Hz, 2H), 7.03-7.08 (m, 1H), 6.80-6.84 (m, 1H), 6.71-6.75(m, 1H), 5.18 (s, 1H), 3.94 (s, 6H), 3.59 (s, 1H), 2.64 (s, 1H),2.41-2.46 (m, 1H), 1.47 (s, 9H). LCMS: m/z=505 [M+H]⁺.

Step E:(R)-1-(3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one(5)

Intermediate 4 (870 mg, 1.73 mmol, 1.0 eq) were dissolved in DCM (30mL), added TFA (2.5 mL) in one portion. The mixture was stirred forabout 1.5 h at rt. Volatile components were removed under vacuum to givethe title product of crude product, and directly used in next stepwithout further purification. The crude product was dissolved in DCM (20mL), added TEA to the solution until PH=8.0, then added Acryloylchloride (187 mg, 2.07 mmol, 1.2 eq) in DCM (3.0 mL) dropwise to thesolution. The reaction mixture was stirred for 0.5 h, poured onto waterand extracted with DCM. The organic layer was dried with anhydrousNa₂SO₄, filtered and concentrated, the residue was purified by silicagel column chromatography (DCM/MeOH=200:1-50:1) to give the titleproduct (400 mg, yield 50.6%). ¹H-NMR (400 MHz, CDCl₃): δ 9.34 (d, J=4.4Hz, 1H), 8.47-8.49 (m, 1H), 7.90-7.94 (m, 2H), 7.34 (d, J=4.8 Hz, 1H),7.12-7.14 (m, 2H), 7.03-7.07 (m, 1H), 6.80-6.84 (m, 1H), 6.71-6.75 (m,1H), 6.40-6.52 (m, 2H), 5.69-5.75 (m, 1H), 5.20-5.23 (m, 1H), 4.06-4.17(m, 3H), 3.94 (s, 3H), 3.81-3.85 (m, 1H), 2.47-2.78 (m, 2H). LCMS:m/z=459.1 [M+H]⁺.

Example 4:(R)-1-(3-(3-(4-(2-chloro-3-fluorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one

Step A:tert-butyl(R)-3-(3-(4-(2-chloro-3-fluorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate(2)

To a solution of 1 (80 mg, 0.22 mmol, 1.0 eq) and corresponding boronicacid (88 mg 0.33 mmol, 1.5 eq) in toluene (10 mL) and water (2 mL) wasadded K₂CO₃ (61 mg, 0.44 mmol, 2.0 eq) and (Ph₃P)₄Pd (25 mg, 0.1 eq)under N₂ with stirring. The mixture was refluxed for 6 h until thematerial was disappeared. The reaction mixture was cooled to roomtemperature. The toluene was removed by rotary evaporation. The residuewas poured into water and extracted with EA. The organic layer was driedover Na₂SO₄, filtered and the solvent was removed by rotary evaporation.The product was purified with flash silica gel chromatography(DCM:MeOH=100:1-50:1), give the title product (90 mg, yield 81%). LCMS:m/z=509 [M+H]⁺

Step B: (R)-1-(3-(3-(4-(2-chloro-3-fluorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one

Intermediate 2 (90 mg, 0.18 mmol, 1.0 eq) were dissolved in DCM (4 mL),added TFA (1 mL) in one portion. The mixture was stirred for about 1.5 hat rt. Volatile components were removed under vacuum to give the titleproduct of crude product which was directly used in next step withoutfurther purification. The crude product was dissolved in DCM (4 mL),added TEA to the solution until PH=8.0, then added Acryloyl chloride (16mg, 0.18 mmol, 1.0 eq) in DCM (1.0 mL) dropwise to the solution. Thereaction mixture was stirred for 0.5 h, poured onto water and extractedwith DCM. The organic layer was dried with anhydrous Na₂SO₄, filteredand concentrated, the residue was purified with silica gel columnchromatography (DCM/MeOH=200:1-50:1) to give the title product (40 mg,yield 50%). ¹H-NMR (400 MHz, CDCl₃): δ 9.35 (d, J=4.1 Hz, 1H), 8.49 (t,J=5.9 Hz, 1H), 7.96 (dd, J=8.2, 6.0 Hz, 2H), 7.41-7.31 (m, 1H),7.25-7.17 (m, 1H), 7.13 (dd, J=8.6, 2.5 Hz, 2H), 7.00 (t, J=8.4 Hz, 1H),6.87 (d, J=8.3 Hz, 1H), 6.48 (ddd, J=14.5, 13.7, 7.2 Hz, 2H), 5.83-5.65(m, 1H), 5.38-5.15 (m, 1H), 4.26-3.94 (m, 3H), 3.95-3.69 (m, 1H),2.85-2.42 (m, 2H). LCMS: m/z=463.2[M+H]⁺.

Example 5: (R)-1-(3-(3-(4-(2-fluoro-3-methoxy phenoxy)phenyl)-7-methyl-1H-pyrazolo [4,3-c]pyridin-1-yl) pyrrolidin-1-yl)prop-2-en-1-one

Step A: 4-(2-fluoro-3-methoxyphenoxy)benzaldehyde (1)

To a solution of 4-bromobenzaldehyde (6.99 g, 38 mmol, 1.2 eq) indioxene (100 mL) was added 2-fluoro-3-methoxyphenol (4.5 g, 32 mmol, 1.0eq), CuI (0.60 g, 3.2 mmol, 0.1 eq), N,N-Dimethylglycine hydrochloride(1.32 g, 9.5 mmol, 0.3 eq), Cs₂CO₃ (20.59 g, 60 mmol, 2 eq). The mixturewas stirred at 100° C. in N₂ for 15 h. The mixture was filtered,contracted and extracted with EtOAc, The organic layer was washed withwater and brine, dried with anhydrous Na₂SO₄, and purified by silica gelcolumn chromatography to give the title product (4.1 g, 52.6%). ¹H-NMR(400 MHz, CDCl₃): δ 9.9 (s, 1H), 7.85-7.83 (m, 2H), 7.26-7.04 (m, 3H),6.89-6.85 (m, 1H), 6.77-6.73 (m, 1H), 3.92 (s, 3H).

Step B: 4,5-dichloropyridin-3-yl) (4-(2-fluoro-3-methoxyphenoxy)phenyl)-methanol (2)

To a solution of diisopropylamine (2.1 mL, 15.1 mmol, 1.1 eq) in dry THF(24 mL) at −78° C. was added a 2.5M BuLi solution in hexane (8.2 mL,20.0 mmol, 1.3 eq). The mixture was allowed to warm to 0° C. and stirredaround 1 h. After this time the solution was cooled to −78° C. and3,4-dichloropyridine (2.0 g, 13.7 mmol, 1 eq) in 5 mL of dry THF wasadded. The reaction mixture was stirred for additional 4 h, and then thecorresponding 4-(2-fluoro-3-methoxyphenoxy)benzaldehyde (3.36 g, 13.7mmol, 1 eq) was added and the mixture was stirred and allowed to warm toroom temperature during overnight. Excess of LDA was destroyed with H₂O(25 mL), and the mixture extracted with Et₂O (3×50 mL). The organicphases were combined, dried over Na₂SO₄, volatile components wereremoved under vacuum and the residue was purified by columnchromatography on silica gel (gradient: DCM/MeOH=200:1-50/1) to give thetitle product (4.5 g, yield 83.6%). ¹H-NMR (400 MHz, CDCl₃): δ 8.78 (s,1H), 8.55 (s, 1H), 7.30 (d, J=8.0 Hz, 2H), 7.02 (d, J=8.0 Hz, 2H),6.98-6.66 (m, 3H), 6.12 (s, 1H), 3.93 (s, 3H). LCMS: m/z=394.1 [M+H]⁺.

Step C: (4,5-dichloropyridin-3-yl)(4-(2-fluoro-3-methoxyphenoxy)phenyl)-methanone (3)

A solution of 4,5-dichloropyridin-3-yl) (4-(2-fluoro-3-methoxy phenoxy)phenyl)methanol (2) (1 g, 2.5 mmol) in dry acetone (10 mL) was cooled to0° C. and CrO₃ (0.92 g, 9.23 mmol) was added carefully in smallportions. The resulting solution was stirred at room temperature untilcomplete consumption of the starting material (3 h), after this time thereaction was quenched with 2-propanol (6 mL), and the mixture wasstirred during 30 min. A saturated solution of NaHCO₃ (50 mL) wasfinally added to precipitate the chromium salts that were filtered overcelite and washed with CH₂Cl₂ (6×15 mL). The solvent were removed undervacuum and the residue was purified by column chromatography on silicagel (gradient: DCM/MeOH=200:1), to give the title product (0.69 g, yield70.7%). LCMS: m/z=392.1 [M+H]⁺.

Step D: 7-chloro-3-(4-(2-fluoro-3-meth oxy phen oxy)phenyl)-1H-pyrazolo[4,3-c]pyridine(4)

To a stirred solution(4-(benzyloxy)phenyl)(4-chloropyridin-3-yl)methanone (3) (0.7 g, 1.77mol) in absolute ethanol (5 ml) was added hydrazine (1.08 g, 17.3 mol).The solution was heated under reflux for 3 h, cooled, the productfiltered off and washed consecutively with water and methanol to givethe title product (0.54 g, yield 83%). ¹H-NMR (400 MHz, CD₃OD): δ 9.30(s, 1H), 8.37 (s, 1H), 8.01 (d, J=8 Hz, 2H), 7.13-7.3.74 (m, 4H), 7.18(d, J=8 Hz, 2H), 3.92 (S, 3H). LCMS: m/z=370.1 [M+H]⁺.

Step E: (R)-tert-butyl 3-(7-chloro-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate (5)

Into a 100 mL 3-necked round-bottom flask, was placed a solution of3-(4-(benzyloxy)phenyl)-1H-pyrazolo[4,3-c]pyridine (4) (0.52 g, 1.41mmol) in N,N-dimethylformamide (41 mL),(S)-tert-butyl-3-(tosyloxy)pyrrolidine-1-carboxylate (0.68 g, 1.99mmol), and Cs₂CO₃ (0.97 g, 2.98 mmol). The resulting solution wasstirred for 12 h at 60° C., and then quenched by the addition of 100 mLof water. The resulting solution was extracted with EA and the organiclayers combined. The organics were washed with brine, dried overanhydrous NaHCO₃, The solvent were removed under vacuum and the residuewas purified by column chromatography on silica gel (gradient:DCM/MeOH=200:1-100:1) to give the title product (0.68 g, yield 90%).LCMS: m/z=539.1 [M+H]⁺.

Step F: ((R)-tert-butyl 3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate(6)

To a solution of (R)-tert-butyl3-(7-chloro-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate (100 mg, 0.18 mmol), methylboronic acid (12.2mg, 0.20 mmol), K₃PO₄. H₂O (102 mg, 0.44 mmol) andtricyclohexylphosphine (10.09 mg, 0.036 mmol) in toluene (10.0 mL) andwater (2 mL) under a nitrogen atmosphere was added diacetoxypalladium (5mg g, 0.018 mmol), The mixture was heated to 100° C. overnight and thencooled to room temperature. Water (100 mL) was added and the mixtureextracted with EtOAc, the combined organics were washed with brine,dried over MgSO₄ and concentrated in vacuo to afford the crude compound.the residue was purified with silica gel column chromatography(DCM/MeOH=200:1-50:1) to give the title product (25 mg, yield 26%).LCMS: m/z=519.1 [M+H]⁺.

Step G: (R)-1-(3-(3-(4-(2-fluoro-3-methoxy phenoxy)phenyl)-7-methyl-1H-pyrazolo [4,3-c]pyridin-1-yl) pyrrolidin-1-yl)prop-2-en-1-one (7)

((R)-tert-butyl 3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate(25 mg, 0.048 mmol) were added to CF₃COOH/DCM=4/1 (5 mL) in one portion.The mixture was stirred for about 1 h at rt. Volatile components wereremoved under vacuum to give the title crude product (20 mg), anddirectly used in next step without further purification. LCMS: m/z=419[M+H]⁺.

A solution of Acryloyl chloride (4.3 mg, 0.048 mmol) in DCM (1 mL) wasadded to a stirred solution of (R)-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-methyl-1-(pyrrolidin-3-yl)-1H-pyrazolo[4,3-c]pyridine (472-7)(20 mg, 0.048 mmol) and TEA (44 mg, 0.43 mmol) in DCM (5 mL) at 0° C.The reaction mixture was stirred for 1 h, poured onto brine andextracted with DCM. The organic layer was dried, concentrated andrecrystallized from DCM/MeOH=100/1 to give the title product (11 mg,yield 50%). ¹H-NMR (400 MHz, CDCl₃): δ 9.18 (br, 1H), 8.21 (br, 1H),7.89-7.86 (m, 2H), 7.26-7.02 (m, 3H), 6.83-6.49 (m, 2H), 6.43-6.41 (m,2H), 5.74-5.71 (m, 1H), 5.34-5.29 (m, 1H), 4.13-3.93 (m, 6H), 2.73-2.19(m, 4H), 2.04-2.00 (m, 2H). LCMS: m/z=473.2 [M+H]⁺.

Example 6:(R)-1-(3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en-1-one

Step A: (4-chloro-5-fluoropyridin-3-yl)(4-(2-fluoro-3-ethoxyphenoxy)phenyl)methanol (1)

To a solution of 4-chloro-3-fluoropyridine (6.4.0 g, 49 mmol, 1.2 eq) inanhydrous THF (100 mL) was added LDA (2 N, 25.6 mL) by dropwise slowlyat −65 degree under nitrogen atmosphere. After the addition wascompleted, the resulting solution was stirred at that temperature for4.0 h. Then a solution of 4-(2-fluoro-3-methoxyphenoxy) benzaldehyde(10.0 g, 41 mmol, 1.0 eq) in anhydrous THF (20 mL) was added carefullyat the same temperature. After the addition, the reaction was stirred atroom temperature (15 degree) for 1.0 h, monitored by TLC and LCMS. Thereaction mixture was quenched by water, then poured into water,extracted with ethyl acetate, washed with water and brine. The organiclayer was dried over anhydrous Na₂SO₄, concentrated under vacuum to givecrude product 1 and used to next step without further purification.LCMS: m/z=378.1 [M+H]⁺.

Step B: (4-chloro-5-fluoropyridin-3-yl)(4-(2-fluoro-3-methoxyphenoxy)phenyl) methanone (2)

To a solution of 1 (10.0 g, (crude), 26.53 mmol, 1.0 eq) in DCM wasadded Dess-Martin (22.5 g, 53.05 mmol, 2.0 eq) by portions slowly underice bath. The resulting solution was stirred at 15 degree for 4.0 h,monitored by TLC and LCMS. The reaction mixture was added the saturationNaHCO₃ solution, then filtrated. The filtrate was poured into water,extracted with DCM, washed with saturation NaHCO₃, Na₂SO₃ solution,water and brine. The organic solution was dried over anhydrous Na₂SO₄,concentrated under vacuum to give crude product 2 (10.0 g) and used tonext step without further purification. LCMS: m/z=376.1 [M+H]⁺.

Step C: 7-fluoro-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridine (3)

To a solution of 2 (48 g, 128 mmol, 1.0 eq) in EtOH (300 mL) was addedN₂H₄.H₂O (64 g, 1.28 mol, 10.0 eq). The resulting solution was stirredat 90 degree for 2.5 h. The reaction was monitored by TLC and LCMS, andthe reaction mixture was cooled to room temperature, then filtrated. Thecake was washed with EtOH and EA, dried under vacuum to give pureproduct 3 (33.3 g). ¹H-NMR (400 MHz, D6-DMSO): δ 9.24-9.23 (d, J 2.0 Hz,1H), 8.39-8.38 (d, J 2.4 Hz, 1H), 8.08-8.06 (d, J 8.8 Hz, 2H), 7.22-7.17(m, 1H), 7.14-7.06 (m, 3H), 6.86-6.82 (m, 1H), 3.90 (s, 3H). LCMS:m/z=354.1[M+H]⁺.

Step D: (R)-tert-butyl3-(7-fluoro-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate (4)

A solution of 3 (20 g, 57 mmol, 1.0 eq), (S)-tert-butyl3-(tosyloxy)piperidine-1-carboxylate (40 g, 113 mmol, 2.0 eq), cesiumcarbonate (37 g, 113 mmol, 2.0 eq) in DMF (20 mL) was stirred at 60degree for 60 h. The reaction was monitored by LC-MS. The reactionmixture was cooled to room temperature, poured into water. The mixturewas extracted with ethyl acetate, washed with water and brine. Theorganic layer was dried over anhydrous Na₂SO₄, concentrated undervacuum. The product was purified by silica gel column chromatography(DCM:MeOH=200:1 to 150:1) to give 4 (17 g). ¹H-NMR (400 MHz, CDCl₃): δ9.09 (s, 1H), 8.30-8.29 (d, J=3.2 Hz, 1H), 7.91-7.89 (d, J 8.4 Hz, 2H),7.14-7.12 (d, J 8.4 Hz, 2H), 7.08-7.03 (m, 1H), 6.84-6.80 (m, 1H),6.74-6.71 (m, 1H), 4.75-4.73 (m, 1H), 4.13-4.11 (m, 3H), 3.93 (s, 3H),3.41-3.38 (m, 1H), 2.92-2.86 (m, 1H), 2.44-2.29 (m, 2H), 1.95-1.86 (m,1H), 1.73-1.70 (m, 1H), 1.47-1.42 (m, 9H). LCMS: m/z=537.2[M+H]⁺.

Step E: (R)-tert-butyl3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate(5)

A solution of 4 (15 g, 28.0 mmol, 1.0 eq), MeONa (15 g, 280 mmol, 10.0eq) in MeOH (120 mL) was added into 250 mL seal tube was stirred at 100degree for overnight. The reaction was monitored by TLC and LC-MS. Thereaction mixture was cooled to room temperature, poured into water,extracted with ethyl acetate, washed with water and brine. The organiclayer was dried over anhydrous Na₂SO₄, concentrated under vacuum to givecrude product. The product was purified by silica gel columnchromatography (DCM:MeOH=150:1 to 100:1) to give 5 (13.2 g). ¹H-NMR (400MHz, CDCl₃): δ 8.94 (s, 1H), 7.99 (s, 1H), 7.91-7.89 (d, J 8.8 Hz, 2H),7.13-7.11 (d, J 8.8 Hz, 2H), 7.06-7.01 (m, 1H), 6.82-6.78 (m, 1H),6.73-6.69 (m, 1H), 5.06-5.04 (m, 1H), 4.14-4.11 (m, 1H), 4.08 (s, 3H),3.93 (s, 3H), 3.37 (s, 1H), 2.89-2.83 (m, 1H), 2.30-2.24 (m, 2H), 1.92(s, 1H), 1.70-1.67 (m, 1H), 1.48-1.44 (m, 11H). LCMS: m/z=549.2[M+H]⁺.

Step F:(R)-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-methoxy-1-(piperidin-3-yl)-1H-pyrazolo[4,3-c]pyridine(6)

To a solution of 5 (13 g, 23.7 mmol) in DCM (100 mL) was added TFA (14mL) at 18 degree for 4.0 h, the reaction was monitored by LC-MS and TLC.The reaction mixture was concentrated under vacuum to give crude product6 (5.5 g) and used to next step without further purification. LCMS:m/z=449.2[M+H]⁺.

Step G:(R)-1-(3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en-1-one(7)

To a solution of 6 (5.5 g, crude), TEA (2.2 g, 21.9 mmol, 2.0 eq) inanhydrous DCM (50 mL) was added acryloyl chloride (40 mg/mL in anhydrousDCM) at −30 deg. The resulting solution was stirred at 18 degree for 30min, monitored by LC-MS and TLC. The reaction mixture was quenched bywater, and then poured into water, extracted with DCM, washed with waterand brine. The organic solution was dried over anhydrous Na₂SO₄,concentrated under vacuum. The product was purified by silica gel columnchromatography (DCM:MeOH=200:1 to 150:1 to 100:1) to give 7 (3.2 g).¹H-NMR (400 MHz, CDCl₃): δ 8.95 (s, 1H), 8.00 (s, 1H), 7.91-7.89 (d, J8.8 Hz, 2H), 7.14-7.11 (d, J 8.4 Hz, 2H), 7.06-7.02 (m, 1H), 6.83-6.79(m, 1H), 6.73-6.70 (m, 1H), 6.64-6.61 (m, 1H), 6.34-6.30 (m, 1H),5.73-5.67 (m, 1H), 5.07-4.66 (m, 2H), 4.29-4.06 (m, 4H), 3.93 (m, 3H),3.625-2.82 (m, 2H), 2.32-1.72 (m, 4H). LCMS: m/z=503.2[M+H]⁺.

The following additional Examples 7-99 shown in the Table below wereprepared following the procedures outlined in the general methods aboveand detailed in Examples 1-6.

MS(calcd) [M + H]⁺/ Entry Structure MS (found) Name 7

461.19/ 461.2 (R)-1-(3-(3-(4-(naphthalen-1-yloxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one 8

469.18/ 469.2 (R)-1-(3-(3-(4-(benzo[d][1,3]dioxol-4-yloxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en-1-one 9

459.15/ 459.2 (R)-1-(3-(3-(4-(3-chlorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin- 1-yl)prop-2-en-1-one 10

425.19/ 425.2 (R)-1-(3-(3-(4-(m-tolyloxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1- yl)prop-2-en-1-one 11

445.14/ 445.2 (R)-1-(3-(3-(3-chloro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1- yl)pyrrolidin-1-yl)prop-2-en-1-one 12

439.21/ 439.2 (R)-1-(3-(3-(4-(2,3- dimethylphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1- yl)prop-2-en-1-one Exact Mass:438.21 13

475.15/ 475.2 (R)-1-(3-(3-(4-(2-chloro-3- methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrroloidin-1- yl)prop-2-en-1-one 14

443.18/ 443.2 (R)-1-(3-(3-(4-(3-fluoro-2-methylphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en- 1-one 15

425.19/ 425.2 1-(4-(3-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- yl)prop-2-en-1-one 16

457.20/ 457.2 (R)-1-(3-(3-(4-(3-fluoro-2-methylphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en-1- one 17

461.17/ 461.2 (R)-1-(3-(3-(4-(2,3- difluorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- yl)prop-2-en-1-one 18

447.16/ 447.2 (R)-1-(3-(3-(4-(2,3- difluorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1- yl)prop-2-en-1-one 19

463.13/ 463.1 (R)-1-(3-(3-(4-(3-chloro-2-fluorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en- 1-one 20

477.14/ 477.1 (R)-1-(3-(3-(4-(3-chloro-2-fluorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en-1- one 21

425.19/ 425.2 1-(3-((3-(4-phenoxyphenyl)-1H- pyraozlo[4,3-c]pyridin-1-yl)methyl)pyrrolidin-1-yl)prop-2-en-1-one 22

433.16/ 433.2 N-(3-(3-(4-phenoxyphenyl)-1H- pyrazolo[4,3-c]pyridin-1-yl)phenyl)acrylamide 23

483.23/ 483.2 (R)-1-(3-(3-(4-(3- isopropoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- yl)prop-2-en-1-one 24

453.22/ 453.2 (R)-1-(3-(3-(4-(2,3- dimethylphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- yl)prop-2-en-1-one 25

501.16/ 501.2 (R)-1-(3-(3-(4-(2-chloro-3- methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- yl)but-2-yn-1-one 26

485.19/ 485.2 1-(6-(3-(4-(2-fluoro-3- methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-2- azaspiro[3.3]heptan-2-yl)prop-2-en-1-one27

493.14/ 493.1 (R)-1-(3-(7-chloro-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-1H- pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one 28

484.17/ 484.2 (R)-1-(1-acryloylpyrrolidin-3-yl)-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridine-7-carbonitrile 29

431.24/ 431.2 (R)-1-(3-(3-(4-(cyclohexyloxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin- 1-yl)prop-2-en-1-one 30

501.16/ 501.2 1-(6-(3-(4-(2-chloro-3- methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)-2- azaspiro[3.3]heptan-2-yl)prop-2-en-1-one31

451.21/ 451.2 (R)-1-(3-(3-(4-((2,3-dihydro-1H-inden-4-yl)oxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en- 1-one 32

458.18/ 458.2 (R)-1-(3-(3-(4-(2-fluoro-3- methoxyphenoxy)phenyl)-1H-pyrazolo[3,4-c]pyridin-1-yl)pyrrolidin-1- yl)prop-2-en-1-one 33

425.19/ 425.2 (R)-1-(3-(3-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- yl)prop-2-en-1-one 34

460.11/460.1 (S)-1-(3-(3-(4-((3- chlorophenyl)thio)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1- yl)prop-2-en-1-one 35

459.15/ 459.2 (S)-1-(3-(3-(3-chloro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin- 1-yl)prop-2-en-1-one 36

445.14/ 445.1 (S)-1-(3-(3-(4-(3-chlorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1- yl)pyrrolidin-1-yl)prop-2-en-1-one 37

439.21/ 439.2 (S)-1-(3-(3-(4-(m-tolyloxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- yl)prop-2-en-1-one 38

463.13/ 463.1 (R)-1-(3-(3-(4-(2-chloro-3-fluorophenoxy)phenyl)-2H-pyrazolo[4,3-c]pyridin-2-yl)pyrrolidin-1-yl)prop-2-en- 1-one 39

477.14/477.2 (R)-1-(3-(3-(4-(2-chloro-3-fluorophenoxy)phenyl)-2H-pyrazolo[4,3-c]pyridin-2-yl)piperidin-1-yl)prop-2-en-1- one 40

477.14/477.2 (S)-1-(3-(3-(4-(2-chloro-3-fluorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en-1- one 41

479.10/479.1 (R)-1-(3-(3-(4-(2,3- dichlorophenoxy)phenyl)-2H-pyrazolo[4,3-c]pyridin-2-yl)pyrrolidin-1- yl)prop-2-en-1-one 42

479.10/479.1 (S)-1-(3-(3-(4-(2,3- dichlorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1- yl)prop-2-en-1-one 43

493.11/493.1 (R)-1-(3-(3-(4-(2,3- dichlorophenoxy)phenyl)-2H-pyrazolo[4,3-c]pyridin-2-yl)piperidin-1- yl)prop-2-en-1-one 44

493.11/493.1 (S)-1-(3-(3-(4-(2,3- dichlorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- yl)prop-2-en-1-one 45

505.22/505.2 (R)-1-(3-(5-acetyl-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one 46

517.22/517.2 (R)-1-(3-(5-acryloyl-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one 47

443.18/443.2 (R)-1-(3-(3-(4-(2-fluoro-3-methylphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en- 1-one 48

457.20/457.2 (R)-1-(3-(3-(4-(2-fluoro-3-methylphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en-1- one 49

459.18/459.2 (R)-1-(3-(3-(4-(3-fluoro-2- methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1- yl)prop-2-en-1-one 50

473.19/473.2 (R)-1-(3-(3-(4-(3-fluoro-2- methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- yl)prop-2-en-1-one 51

443.18/443.2 (R)-1-(3-(3-(3-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin- 1-yl)prop-2-en-1-one 52

397-16/397.2 1-(3-(3-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)azetidin-1- yl)prop-2-en-1-one 53

439.21/439-2 1-(3-((3-(4-phenoxyphenyl)-1H- pyrazolo[4,3-c]pyridin-1-yl)methyl)piperidin-1-yl)prop-2-en-1-one 54

425.19/425.2 (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-indazol-1-yl)pyrrolidin-1-yl)prop-2- en-1-one 55

439.21/439-2 (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-indazol-1-yl)piperidin-1-yl)prop-2-en- 1-one 56

473.17/473.2 (R)-1-(3-(3-(4-(3-chloro-2-methylphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en-1- one 57

469.22/469.2 (R)-1-(3-(3-(4-(3-methoxy-2-methylphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en-1- one 58

445.14/445.1 (R)-1-(3-(3-(4-((3- fluorophenyl)thio)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1- yl)prop-2-en-1-one 59

455.20/455.2 (R)-1-(3-(3-(4-(3-methoxy-2-methylphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en- 1-one 60

459.15/459.2 (R)-1-(3-(3-(4-(3-chloro-2-methylphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en- 1-one 61

429.16/429.2 (R)-1-(3-(3-(3-fluoro-4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1- yl)pyrrolidin-1-yl)prop-2-en-1-one 62

443.18/443.2 (R)-1-(3-(3-(4-(3-fluorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin- 1-yl)prop-2-en-1-one 63

429.16/429.2 (R)-1-(3-(3-(4-(3-fluorophenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1- yl)pyrrolidin-1-yl)prop-2-en-1-one 64

441.18/441.2 (R)-1-(3-(3-(4-(3- methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1- yl)prop-2-en-1-one 65

455.20/455.2 (R)-1-(3-(3-(4-(3- methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- yl)prop-2-en-1-one 66

429.46/429.1 (R)-1-(3-(7-fluoro-3-(4-phenoxyphenyl)-1H- pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en- 1-one 67

509.49/509.1 (R)-1-(3-(7-difluoromethyl)-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)- 1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one 68

493.93/493.2 R)-1-(3-(3-(4-(2-chloro-3-methoxyphenoxy)phenyl)-7-fluoro-1H- pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en- 1-one 69

505.96/505.2 (R)-1-(3-(3-(4-(2-chloro-3-methoxyphenoxy)phenyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1- yl)prop-2-en-1-one 70

491.5/491.1 (R)-1-(3-(7-fluoro-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-1H- pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en-1-one 71

473.19/ 473.2 (R)-1-(3-(3-(4-(2-fluoro-3- methoxyphenoxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- yl)prop-2-en-1-one 72

523.52/523.2 (R)-1-(3-(7-difluoromethyl)-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)- 1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en-1-one 73

517.56/517.2 (R)-1-(3-(7-ethoxy-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)- 1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en-1-one 74

726.83/726.3 (R)-(3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-methoxy-1H- pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)(2-tosyl-2-azaspiro[3.3]heptan-6-yl)methanone 75

519.99/520.1 (R)-1-(3-(3-(4-(2-chloro-3-methoxyphenoxy)phenyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- yl)prop-2-en-1-one 76

545.62/545.2 (R)-1-(3-(7-butoxy-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)- 1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en-1-one 77

531.59/531.1 (R)-1-(3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-propoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- yl)prop-2-en-1-one 78

487.54/487.1 (R)-1-(3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-4-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- yl)prop-2-en-1-one 79

489.51/489.2 (R)-1-(3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1- yl)prop-2-en-1-one 80

503.54/503.2 (R)-1-(3-(7-ethoxy-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)- 1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one 81

534.01/534.1 (R)-1-(3-(3-(4-(2-chloro-3-methoxyphenoxy)phenyl)-7-ethoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- yl)prop-2-en-1-one 82

489.51/489.2 (R)-1-(3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-hydroxy-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- yl)prop-2-en-1-one 83

548.04/548.1 (R)-1-(3-(3-(4-(2-chloro-3-methoxyphenoxy)phenyl)-7-propoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- yl)prop-2-en-1-one 84

562.07/562.0 (R)-1-(3-(7-butoxy-3-(4-(2-chloro-3-methoxyphenoxy)phenyl)- 1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en-1-one 85

548.04/548.1 (R)-1-(3-(3-(4-(2-chloro-3-methoxyphenoxy)phenyl)-7-isopropoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- yl)prop-2-en-1-one 86

576.05/576.0 1-((3R)-3-(3-(4-(2-chloro-3- methoxyphenoxy)phenyl)-7-((tetrahydrofuran-3-yl) oxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en-1-one 87

532.58/532.1 (R)-1-(3-(7-(2-aminoethoxy)-3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)- 1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en-1-one 88

571.68/571.2 (R)-1-(3-(3-(4-(3-methoxy-2-propoxyphenoxy)phenyl)-7-propoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- yl)prop-2-en-1-one 89

505.55/505.1 (R)-1-(3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- yl)propan-1-one 90

584.65/584.2 (R,E)-2-(3-(3-(4-(2-fluoro-3- methoxyphenoxy)phenyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridin-1- yl)piperidine-1-carbonyl)-4,4-dimethylpent- 2-enenitrile 91

503.54/503.3 1-(2-((3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-methoxy-1H- pyrazolo[4,3-c]pyridin-1-yl)methyl)pyrrolidin-1-yl)prop-2-en-1-one 92

584.65/584.3 (E)-2-(2-((3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-methoxy-1H- pyrazolo[4,3-c]pyridin-1-yl)methyl)pyrrolidine-1-carbonyl)-4,4- dimethylpent-2-enentrile 93

560.63/560.2 (R)-1-(3-(7-(2-(dimethylamino)ethoxy)-3-(4-(2-fluoro-3-methoxyphenoxy) phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en-1-one 94

572.64/572.1 (R)-1-(3-(7-(2-(dimethylamino)ethoxy)-3-(4-(2-fluoro-3-methoxyphenoxy) phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)but-2-yn-1-one 95

435.53/435.1 (S)-1-(3-(3-(4-(1-phenylvinyl)phenyl)-1H- pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en- 1-one 96

531.59/531.1 (R)-1-(3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-isopropoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- yl)prop-2-en-1-one 97

519.99/520.0 (R)-1-(3-(3-(4-(2-chloro-3-methoxyphenoxy)phenyl)-7-ethoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1- yl)prop-2-en-1-one 98

533.56/533.1 (R)-1-(3-(3-(4-(2-fluoro-3- methoxyphenoxy)phenyl)-7-(2-hydroxyethoxy)- 1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en-1-one 99

559.6/559.3 1-((3R)-3-(3-(4-(2-fluoro-3- methoxyphenoxy)phenyl)-7-((tetrahydrofuran-3-yl) oxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en-1-one

Example 100:(R)-1-(3-(3-(4-((2-fluorobenzyl)oxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one

Step A: (R)-tert-butyl3-(3-(4-((2-fluorobenzyl)oxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl) pyrrolidine-1-carboxylate (1)

Into a 100 mL round-bottom flask was placed a solution of(R)-tert-butyl-3-(3-(4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate(30 mg, 0.078 mmol) in DMF (3 mL), 1-(bromomethyl)-2-fluorobenzene (22mg, 0.117 mmol), and Cs₂CO₃ (51.3 mg, 0.16 mmol). The resulting solutionwas stirred for 3 h at rt. and then quenched by the addition of 100 mLof water. The resulting solution was extracted with EtOAc and theorganic layers combined. The organics were washed with brine, dried overanhydrous Na₂SO₄, The solvent were removed under vacuum and the residuewas purified by column chromatography on silica gel (gradient:DCM/MeOH===200:1-100:1) to give the title product (30 mg, yield 80%).LCMS: m/z=489.2 [M+H]⁺.

Step B:(R)-1-(3-(3-(4-((2-fluorobenzyl)oxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one (2)

((R)-tert-butyl 3-(3-(4-(2-fluoro-3-methoxyphenoxy)phenyl)-7-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate(30 mg, 0.061 mmol) were added to CF₃COOH/DCM=4/1 (5 mL) in one portion.The mixture was stirred for about 1 h at rt. Volatile components wereremoved under vacuum to give the title product of crude product (24 mg),and directly used in next step without further purification. LCMS:m/z=389.2 [M+H]⁺.

A solution of Acryloyl chloride (5.5 mg, 0.061 mmol) in DCM (1 mL) wasadded to a stirred solution of (R)-3-(4-((2-fluorobenzyl) oxy)phenyl)-1-(pyrrolidin-3-yl)-1H-pyrazolo[4,3-c]pyridine (24 mg, 0.061mmol) and TEA (44 mg, 0.43 mmol) in DCM (5 mL) at 0° C. The reactionmixture was stirred for 1 h, poured onto brine and extracted with DCM.The organic layer was dried, concentrated and recrystallized fromDCM/MeOH===100/1 to give the title product (13 mg, yield 50%). ¹H-NMR(400 MHz, CDCl₃): δ 9.18 (br, 1H), 8.48 (br, 1H), 7.93-7.89 (m, 2H),7.55-7.52 (m, 1H), 7.34-7.26 (m, 2H), 7.20-7.09 (m, 4H), 6.52-6.40 (m,2H), 5.75-5.70 (m, 1H), 5.27-5.23 (m, 1H), 5.22 (s, 1H), 4.16-4.07 (m,3H), 3.82-3.80 (m, 1H), 2.89-2.49 (m, 2H). LCMS: m/z=443.2 [M+H]⁺.

The following additional Example 101, 102 shown in the Table below wereprepared following the procedures outlined in the general methods aboveand detailed in Example 100.

MS(cald) [M + H]⁺/ Entry Structure MS (found) Name 101

457.20/ 457.2 (R)-1-(3-(3-(4-((2- fluorobenzyl)oxy)phenyl)-1H-pyrazolo[4,3-c]pyridin-1- yl)piperidin-1-yl)prop-2-en-1-one 102

438.52/438.00 (R)-1-(3-(3-(4- (phenoxymethyl)phenyl)-1H-indazol-1-yl)piperidin-1-yl)prop- 2-en-1-one

Example 103:(R)-4-(1-(1-acryloylpyrrolidine-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-(3-methoxybenzyl)benzamide

Step A: (R)-tert-butyl3-(3-(4-(methoxycarbonyl)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate(1)

To a solution of (R)-tert-butyl3-(3-bromo-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate (105mg, 0.286 mmol, 1.0 eq) and (4-(methoxycarbonyl)phenyl)boronic acid (77mg, 0.429 mmol, 1.5 eq) in dioxane (8.0 mL) and water (1.0 mL), wasadded K₂CO₃ (79 mg, 0.572 mmol, 2.0 eq) and (Ph₃P)₄Pd (20 mg) under N₂with stirring. The mixture was refluxed for 5.5 h until the material wasdisappeared. The reaction mixture was cooled to room temperature. Thedioxane was removed by rotary evaporation. The residue was poured intowater and extracted with EA. The organic layer was dried over Na₂SO₄,filtered and the solvent was removed by vacuum and the residue waspurified with flash silica gel chromatography (DCM:MeOH=100:1-50:1) togive the title product (90 mg, yield 77.4%). ¹H-NMR (400 MHz, CDCl₃): δ9.45 (s, 1H), 8.53 (s, 1H), 8.19 (d, J=8.4 Hz, 2H), 8.04-8.11 (m, 3H),5.20 (s, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 3.61 (s, 1H), 2.62-2.66 (m,1H), 2.46 (d, J=6.0 Hz, 1H), 1.48 (s, 9H). LCMS: m/z=423 [M+H]⁺.

Step B:(R)-4-(1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)benzoicacid (2)

To a solution of 1 (90 mg, 0.213 mmol, 1.0 eq) in THF (5.0 mL) and EtOH(5.0 mL), LiOH (45 mg, 1.067 mmol, 5.0 eq) was added. The mixture wasstirred at room temperature until the start material disappeared, addedwater, then 1 N HCl was added to adjust to pH=5.0, then the mixture wasextracted with EA, The organic layer was washed with water and brine,dried with anhydrous Na₂SO₄, filtered and concentrated give the titlecrude product 2 (75 mg, 86.2%) used next step without purification.LCMS: m/z=409 [M+H]⁺.

Step C: (R)-tert-butyl3-(3-(4-((3-methoxybenzyl)carbamoyl)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate(3)

Into a 50 mL round-bottom flask, was placed a solution of 2 (75 mg,0.184 mmol, 1.0 eq) in THF (5.0 mL), (3-methoxyphenyl)methanamine (38mg, 0.276 mmol, 1.5 eq), and TEA (47 mg, 0.460 mmol, 2.5 eq), HATU (84mg, 0.221 mmol, 1.2 eq). The resulting solution was stirred for 1.5 h atroom temperature. The reaction mixture was quenched with 30 mL water.The resulting solution was extracted with EA (20 mL*3) and the organiclayers were combined and washed with brine, dried over anhydrous Na₂SO₄,The solvent were removed under vacuum and the residue was purified bysilica gel column chromatography (DCM/MeOH=100:1-50:1) to give the titleproduct (85 mg, yield 87.7%). ¹H-NMR (400 MHz, CDCl₃): δ 9.37 (s, 1H),8.48 (s, 1H), 8.07 (d, J=7.6 Hz, 1H), 7.94 (d, J=7.6 Hz, 1H), 7.38 (s,1H), 7.26-7.32 (m, 1H), 6.94-6.99 (m, 2H), 6.86 (d, J=8.4 Hz, 1H), 6.48(s, 1H), 5.19 (s, 1H), 4.67 (d, J=5.2 Hz, 2H), 3.78-3.93 (m, 6H), 3.60(s, 1H), 2.64 (d, J=6.0 Hz, 1H), 2.46 (d, J=7.6 Hz, 1H), 1.47 (s, 9H).LCMS: m/z=528 [M+H]⁺.

Step D:(R)-4-(1-(1-acryloylpyrrolidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-(3-methoxybenzyl)benzamide(4)

Intermediate 3 (85 mg, 0.157 mmol, 1.0 eq) were dissolved in DCM (8.0mL), added TFA (1.5 mL) in one portion. The mixture was stirred forabout 1.5 h at rt. Volatile components were removed under vacuum to givethe title product of crude product TFA salt, and directly used in nextstep without further purification. The crude product was dissolved inDCM (7.0 mL), added TEA to the solution until PH=8.0, then addedAcryloyl chloride (17 mg, 0.188 mmol, 1.2 eq) in DCM (1.0 mL) dropwiseto the solution. The reaction mixture was stirred for 0.5 h, poured ontowater and extracted with DCM. The organic layer was dried with anhydrousNa₂SO₄, filtered and concentrated, the residue was purified with silicagel plate (DCM/MeOH=50:1) to give the title product (20 mg, yield25.8%). ¹H-NMR (400 MHz, CD₃OD): δ 9.82 (s, 1H), 8.62 (s, 1H), 8.35 (d,J=6.0 Hz, 1H), 8.18 (d, J=8.0 Hz, 2H), 8.08 (d, J=8.0 Hz, 2H), 7.25-7.29(m, 1H), 6.97 (d, J=8.0 Hz, 2H), 6.84 (d, J=8.0 Hz, 1H), 6.61-6.79 (m,1H), 6.32-6.38 (m, 1H), 5.77-5.85 (m, 2H), 4.60 (s, 2H), 4.28 (d, J=4.0Hz, 1H), 4.00 (d, J=6.8 Hz, 1H), 3.80 (s, 3H), 2.62-2.75 (m, 2H). LCMS:m/z=482.2 [M+H]⁺.

The following additional Example 104-105 shown in the Table below wereprepared following the procedures outlined in the general methods aboveand detailed in Example 103.

MS(calc) [M + H]⁺/ Entry Structure MS (found) Name 104

496.23/ 496.2 (R)-4-(1-(1-acryloylpiperidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3- yl)-N-(3- methoxybenzyl)benzamide 105

465.52/465.2 (R)-4-(1-(1-(but-2-ynoyl)piperidin-3- yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-(pyridin-2- yl)benzamide

Example 106:(R)-1-(3-(3-(3′-methyl-[1,1′-biphenyl]-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en-1-one

Step A: (R)-tert-butyl3-(3-(3′-methyl-[1,1′-biphenyl]-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate(1)

To a solution of (R)-tert-butyl3-(3-bromo-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate (66.5mg, 0.175 mmol, 1.0 eq) and (3′-methyl-[1,1′-biphenyl]-4-yl) boronicacid (55.5 mg, 0.262 mmol, 1.5 eq) in dioxane (7.0 mL) and water (1.0mL), was added K₂CO₃ (60.4 mg, 0.436 mmol, 2.0 eq) and Pd[Ph₃P]4 (15 mg)under N₂ with stirring. The mixture was refluxed for 6.0 h and thereaction mixture was cooled to room temperature. The dioxane was removedby rotary evaporation. The residue was poured into water and extractedwith EA. The organic layer was dried over Na₂SO₄, filtered and thesolvent was removed by rotary evaporation. The product was purified withflash silica gel chromatography (DCM:MeOH=100:1-50:1), give the titleproduct (70 mg, yield 85.7%). LCMS: m/z=469 [M+H]⁺.

Step B:(R)-1-(3-(3-(3′-methyl-[1,1′-biphenyl]-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en-1-one(2)

Intermediate 1 (70 mg, 0.15 mmol, 1.0 eq) were dissolved in DCM (5.0mL), added TFA (1.0 mL) in one portion. The mixture was stirred forabout 1.5 h at rt. Volatile components were removed under vacuum to givethe title crude product TFA salt, and directly used in next step withoutfurther purification. The crude product was dissolved in DCM (5.0 mL),added TEA until PH=8.0, then added Acryloyl chloride (20 mg, 0.224 mmol,1.5 eq) in DCM (1.0 mL) dropwise to the solution. The reaction mixturewas stirred for 0.5 h, poured onto water and extracted with DCM. Theorganic layer was dried with anhydrous Na₂SO₄, filtered andconcentrated, the residue was purified with silica gel plate(DCM/MeOH=50:1) to give the title product (20 mg, yield 31.7%). ¹H-NMR(400 MHz, CDCl₃): δ 9.40 (s, 1H), 8.48 (s, 1H), 8.06 (d, J=8.0 Hz, 2H),7.76 (d, J=8.4 Hz, 2H), 7.35-7.48 (m, 4H), 7.20 (d, J=7.6 Hz, 1H),6.56-6.69 (m, 1H), 6.34-6.39 (m, 1H), 5.70-5.78 (m, 1H), 4.95 (d, J=11.2Hz, 0.5H), 4.66 (d, J=7.2 Hz, 0.5H), 4.50 (d, J=10.4 Hz, 1H), 4.08-4.23(m, 1H), 3.84 (s, 0.5H), 3.21-3.30 (m, 1H), 2.93 (s, 0.5), 2.30 (d,J=11.2 Hz, 1H), 1.74 (s, 1H). LCMS: m/z=423 [M+H]⁺.

The following additional Examples 107-115 shown in the Table below wereprepared following the procedures outlined in the general methods aboveand detailed in Examples 106.

MS(cald) [M + H]⁺/ Entry Structure MS (found) Name 107

409.20/ 409.2 (R)-1-(3-(3-(3′-methyl-[1,1′-biphenyl]-4-yl)-1H-pyrazolo[4,3-c]pyridin-1- yl)pyrrolidin-1-yl)prop-2-en-1-one108

409.20/ 409.2 (R)-1-(3-(3-(3′-methyl-[1,1′-biphenyl]-4-yl)-2H-pyrazolo[4,3-c]pyridin-2- yl)pyrrolidin-1-yl)prop-2-en-1-one109

431.55/431.1 (R)-1-(3-(3-(4-(4-methylpiperazin-1- yl)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2- en-1-one 110

499.66/499.3 (R)-1-(3-(3-(4-([1,4′-bipiperidin]-1′-yl)phenyl)-1H-pyrazolo [4,3-c]pyridin-1-yl)piperidin-1-yl)prop-2-en-1-one 111

449.54/449.1 (R)-1-(3-(3-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- yl)prop-2-en-1-one 112

417.52/417.1 (R)-1-(3-(3-(4-(4-methylpiperazin-1- yl)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop- 2-en-1-one 113

461.57/461.3 (R)-1-(3-(3-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- yl)prop-2-en-1-one 114

446.56/446.1 (R)-1-(3-(3-((4-(4-methylpiperazin-1- yl)phenyl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- yl)prop-2-en-1-one 115

495.61/495.2 (R)-1-(3-(3-(4-(4- (methylsulfonyl)piperazin-1-yl)phenyl)-1H- pyrazolo[4,3-c]pyridin-1-yl)piperidin-1- yl)prop-2-en-1-one

Example 116:N-{4-[1-(1-Acryloyl-pyrrolidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-phenyl}-3-trifluoromethyl-benzamide

Step A: (R)-tert-butyl3-(3-(4-aminophenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate(1)

To a solution of (R)-tert-butyl3-(3-bromo-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate (77mg, 0.209 mmol, 1.0 eq) and (4-aminophenyl)-boronic acid (57 mg, 0.418mmol, 2.0 eq) in dioxane (8.0 mL) and water (1.0 mL), was added K₂CO₃(87 mg, 0.628 mmol, 3.0 eq) and (Ph₃P)₄Pd (20 mg) under N₂ withstirring. The mixture was refluxed for 5.5 h until the material wasdisappeared. The reaction mixture was cooled to room temperature. Thedioxane was removed by rotary evaporation. The residue was poured intowater and extracted with EA. The organic layer was dried over Na₂SO₄,filtered and the solvent was removed by vacuum and the residue waspurified by flash silica gel chromatography (DCM:MeOH=100:1-50:1), givethe title product (77 mg, yield 96.8%). LCMS: m/z=380 [M+H]⁺.

Step B: (R)-tert-butyl3-(3-(4-((3-(trifluoromethyl)phenyl)amino)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate(2)

To a solution of 1 (77 mg, 0.203 mmol, 1.0 eq) in DCM (5.0 mL),3-(trifluoromethyl)benzoyl chloride (51 mg, 0.243 mmol, 1.2 eq) whichwas dissolved in DCM (2.0 mL) added, dropwise. The mixture was stirredat room temperature for 2.0 h, added water, then the mixture wasextracted with DCM, The organic layer was washed with water and brine,dried with anhydrous Na₂SO₄, filtered and concentrated. The product waspurified with flash silica gel chromatography (DCM:MeOH=100:1-50:1),give the title product (60 mg, 56.5%). LCMS: m/z=524 [M+H]⁺.

Step C:(R)-1-(3-(3-(4-((3-(trifluoromethyl)phenyl)amino)phenyl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one(3)

Intermediate 2 (60 mg, 0.115 mmol, 1.0 eq) were dissolved in DCM (8.0mL), added TFA (1.0 mL) in one portion. The mixture was stirred forabout 1.5 h at rt. Volatile components were removed under vacuum to givethe title crude product TFA salt, and directly used in next step withoutfurther purification. The crude product was dissolved in DCM (5.0 mL),added TEA until PH=8.0, then added Acryloyl chloride (12 mg, 0.133 mmol,1.2 eq) in DCM (1.0 mL) drop wise to the solution. The reaction mixturewas stirred for 0.5 h, poured onto water and extracted with DCM. Theorganic layer was dried with anhydrous Na₂SO₄, filtered andconcentrated, the residue was purified with silica gel plate(DCM/MeOH=50:1) to give the title product (19 mg, yield 34.7%). ¹H-NMR(400 MHz, CDCl₃): δ 9.34 (d, J=14.0 Hz, 1H), 9.09 (d, J=6.0 Hz, 1H),8.15-8.47 (m, 3H), 7.77-7.95 (m, 5H), 7.58-7.62 (m, 1H), 7.35-7.39 (m,1H), 6.37-6.54 (m, 2H), 5.69-5.75 (m, 1H), 5.21-5.30 (m, 1H), 4.38 (d,J=9.6 Hz, 1H), 4.01-4.18 (m, 3H), 3.80-3.85 (m, 1H), 2.47-2.75 (m, 2H).LCMS: m/z=506.2 [M+H]⁺.

The following additional Example 117 shown in the Table below wereprepared following the procedures outlined in the general methods aboveand detailed in Example 116.

MS(cald) [M + H]⁺/ Entry Structure MS (found) Name 117

520.19/ 520.2 (R)-N-(4-(1-(1-acryloylpiperidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-3- yl)phenyl)-3-(trifluoromethyl)benzamide

The following additional Other examples 118-123 in the Table below wereprepared following the procedures in the general methods from above orreported literature.

MS(cald) [M + H]⁺/ Entry Structure MS (found) Name 118

521.55/521.1 1-((R)-3-(3-(4-(2-fluoro-3- methoxyphenoxy)phenyl)-7-methoxy-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidin-1-yl)-2-hydroxypropan-1-one 119

521.51/521.2 (R)-2-(3-(3-(4-(2-fluoro-3- methoxyphenoxy)phenyl)-7-methoxy-1H-pyrazolo[4,3- c]pyridin- 1-yl)piperidin-1-yl)-2-oxoaceticacid 120

520.52/520.5 (R)-2-(3-(3-(4-(2-fluoro-3- methoxyphenoxy)phenyl)-7-methoxy-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidin-1-yl)-2- oxoacetamide121

492.51/492.2 (3R)-3-(3-(4-(2-fluoro-3- methoxyphenoxy)phenyl)-7-methoxy-1H-pyrazolo[4,3-c] pyridin-1- yl)cyclohexanecarboxylic acid122

492.51/492.2 4-(3-(4-(2-fluoro-3- methoxyphenoxy)phenyl)-7-methoxy-1H-pyrazolo[4,3- c]pyridin-1- yl)cyclohexanecarboxylic acid 123

441.49/441.0 4-(3-(4-benzamidophenyl)-1H- pyrazolo[4,3-c]pyridin-1-yl)cyclohexanecarboxylic acid 124

398.47/398.1 4-(3-([1,1′-biphenyl]-4-yl)-1H- pyrazolo[4,3-c] pyridin-1-yl)cyclohexanecarboxylic acid 125

428.50/428.2 4-(3-(4-(benzyloxy)phenyl)-1H- pyrazolo[4,3-c]pyridin-1-yl)cyclohexanecarboxylic acid 126

414.47/414.1 3-(3-(4-phenoxyphenyl)-1H- pyrazolo[4,3-c]pyridin-1-yl)cyclohexanecarboxylic acid

Btk Kinase Assay and Other Kinases Assay

Btk kinase activity was determined using a homogenous time resolvedfluorescence (HTRF) methodology. Measurements were performed in areaction volume of 15 μL using 384-well assay plates. Kinase enzyme,inhibitor, ATP and 1 μM peptide substrate were incubated in a reactionbuffer compose of Hepes50 mM (pH7.0), NaN3 0.02%, BSA 0.01%,Orthocanadate 0.1 mM. After one hour, the kinase reaction was quenchedby the addition of E t-labeled antibody and XL-665 in 1×Detection buffercontaining 60 mM EDTA (Cisbio), and the mixture was allowed to incubatefor one hour. The HTRF signal was measured on a multimode plate reader(EnVision Multilabel Reader, Perkin Elmer) with an excitation wavelength(λ_(Ex)) of 330 nm and detection wavelengths (λ_(Em)) of 615 and 665 nm.Activity was determined by the ratio of the fluorescence at 665 nm tothat at 615 nm. For each compound, enzyme activity as measured atvarious concentrations of compound, Negative control reactions wereperformed in the absence of inhibitor in two replicates and eight noenzyme controls were used to determine baseline fluorescence levels.IC_(50s) were obtained according to the equation:

Y=100/(1+10{circumflex over ( )}((Log IC50−X)*HillSlope)).

For BTK assay, [ATP]=80 μM, BTK=3.4 nM.

For LYN assay, [ATP]=20 μM, LYN=0.12 n M. For LCK assay, [ATP]=20 μM,LCK=0.2 nM. For BLK assay, [ATP]=20 μM, BLK=0.6 n M.

Example 127

The following Table shows the activity of selected compounds of thisinvention in the BTK inhibition assay. The compound numbers correspondto the compound numbers in previous Tables. Compounds having an activitydesignated as “A” provided an IC 50≤10 nM; Compounds having an activitydesignated as “B” provided an IC₅₀ 10-100 nM; Compounds having anactivity designated as “C” provided an IC₅₀ 100-1000 nM; Compoundshaving an activity designated as “D” provided an IC₅₀ 1000-10000 nM;Compounds having an activity designated as “E” provided an IC₅₀≥10000nM.

BTK Inhibition Data Compound BTK Compound BTK Compound BTK Compound BTK# Inhibition # Inhibition # Inhibition # Inhibition 1 A 2 A 3 A 4 A 5 A6 A 7 B 8 C 9 B 10 B 11 A 12 B 13 A 14 B 15 C 16 B 17 A 18 A 19 A 20 A21 B 22 B 23 B 24 A 25 C 26 A 27 B 28 A 29 B 30 C 31 B 32 B 33 A 34 C 35B 36 B 37 B 38 B 39 B 40 B 41 A 42 A 43 A 44 A 45 D 46 E 47 A 48 B 49 B50 B 51 B 52 B 53 B 54 B 55 B 56 B 57 B 58 A 59 B 60 B 61 A 62 A 63 A 64A 65 B 66 A 67 A 68 A 69 A 70 A 71 A 72 B 73 A 74 C 75 A 76 A 77 A 78 A79 A 80 A 81 A 82 A 83 A 84 A 85 A 86 A 87 B 88 B 89 C 90 B 91 A 92 B 93A 94 B 95 B 96 B 97 A 98 A 99 A 100 B 101 B 102 B 103 C 104 C 105 C 106C 107 B 108 C 109 C 110 B 111 C 112 C 113 C 114 D 115 C 116 B 117 B 118B 119 B 120 B 121 B 122 A 123 E 124 E 125 N/A 126 N/A

Example 128

The following Table shows the activity of selected compounds of thisinvention in the BTK, BLK, LYN, LCK inhibition assay. The compoundnumbers correspond to the compound numbers in previous Tables. Compoundshaving an activity designated as “A” provided an IC₅₀≤10 nM; Compoundshaving an activity designated as “B” provided an IC₅₀ 10-100 nM;Compounds having an activity designated as “C” provided an IC₅₀ 100-1000nM; Compounds having an activity designated as “D” provided an IC₅₀1000-10000 nM; Compounds having an activity designated as “E” providedan IC₅₀≥10000 nM; N/A is not available.

TABLE 2 EGFR Compound BTK IC₅₀ BLK IC₅₀ LYN IC₅₀ LCK IC₅₀ IC₅₀ 1 A A E DC 6 A B D D C

Calcium FluxAssay

Calcium flux fluorescence-based assays were performed in aFDSS7000EX(Hamamatsu Photonics) fluorometric imaging plate reader according tomanufacturer instructions. Compounds to be assayed were dissolved inDMSO, diluted to appropriate concentrations in Ca²⁺ buffer ranging from0 to 10 μM (at a dilution factor of 0.1), added 5 μl (6 X) to each well(the final DMSO concentration was 0.1% in each well). Then 12.5 μL 2×dye loading solution (Fluo-4 NW Calcium Assay Kits, Invitrogen) wasadded per well of a 384-well plate. Afterwards, actively growing Ramoscells (ATCC) in RPM1640 medium supplemented with 10% FBS (Invitrogen)were washed and re-plated in assay buffer (from Fluo-4 NW Calcium AssayKits, Invitrogen) to approximately 6.4×10⁶/ml (80000 cells/12.5 μL in384-well plates). The plates were incubated at 37° C. for 30 minutes,then at room temperature for an additional 30 minutes. The plates werenow ready to be used in an experiment. Immediately after the transferand a 10-s recording of baseline fluorescence, the compound treatedcells were stimulated with a goat anti-human IgM antibody (10 g/ml;Jackson Immuno Research) and read in a FDSS for 240 seconds. Differencebetween the signal and that at baseline, designated adjusted relativefluorescence unit, was calculated by using a custom Excel (Microsoft,Redmond, Wash.) template to determine IgM-induced calcium influx and itsinhibition by compounds. The table below show the result. Compoundshaving an activity designated as “A” provided an IC 50≤10 nM; Compoundshaving an activity designated as “B” provided an IC 50 10-100 nM;Compounds having an activity designated as “C” provided an IC₅₀ 100-1000nM.

TABLE 3 Compound Ramos Ca Flux (nM) Example 1 B Example 2 B Example 3 BExample 4 B Example 6 B Example 11 C Example 17 B Example 18 B Example19 B Example 20 B Example 41 B Example 43 B Example 58 B Example 61 CExample 62 C Example 63 C Example 64 B

Btk Occupancy in Cellular Assays

For PCI-33380 labeling of human B cells, 10⁶ Jeko-1 cells werepre-incubated with compound for 1.5 h before labeling. Then cells weretreated with PCI-33380 at 5 μM for 1 h. Washed, lysed in Ripa buffercontaining sample reducing agent, and analyzed by SDS/PAGE andfluorescent gel scanning using a Typhoon scanner 9500 (GE Healthcare)(Ex, 532 nm; Em, 555 nm). The gel was then blotted and total Btk levelsdetected by standard Western blot with Btk antibody (CST). By using thefluorescently tagged derivative PCI-33380, we found that 25 nM ofcompound 77; 50 nM of compound 3, 78, 79, 80, 83, 100 nM of Compound 2,4, 17, 41, 43, 69, 71, 73, 98 and 99 were sufficient to fully occupy theactive site of Btk in human mantle cell lymphoma cell lines Jeko-1 cellsin culture.

Btk Occupancy In Vivo

For analysis of Btk occupancy in Babc/L mice following oral dosing ofcompounds after 4 hours. Isolating peripheral blood mononuclear cells(PBMCs) with mouse peripheral blood separation kit (Hao Yang BiologicalManufacture CO., LTD, Tianjin) were collected from Babc/L mice (1 mlblood from two mice). Spleens were processed to splenocytes followed by5 min incubation in red blood cell lysing buffer (from mouse peripheralblood separation kit). PBMCs or splenocytes were then PCI-33380-labeledand lysates analyzed by fluorescent gel scanning as described incellular assays. Compound 2, 3, 4, 71 were achieved full occupancy at 10mg/kg single oral dose in all Babc/L mice. Compound 73, 91 were achievedfull occupancy at 5 mg/kg single oral dose in all Babc/L mice.

What is claimed is:
 1. A compound of Formula (I) having the followingstructure:

wherein: A is N or CH; B, C, and D are each N or C—R¹, with the provisothat only one or two of A, B, C, and D can be N; R¹ is hydrogen,halogen, OH, CN, C₁₋₆alkyl, C₁₋₄alkoxy, C₁₋₆alkyl substituted with oneto five fluorines, C₁₋₄alkoxy substituted with one to five fluorines,C₁₋₄alkoxy substituted with OH, C₁₋₄alkoxy substituted with NH₂ orN(CH₃)₂, or

R² is

X-E is one of the followings: (1) X is O, OCR^(a)R^(b), CR^(a)R^(b)O,S(O), S(O)₂, CR^(a)R^(b), NR(C═O), C═ONR^(c) or a bond; and E is ahydrogen, an aryl or a heteroaryl substituted with one to three R⁵substituents; or a 3-7 membered saturated or partially unsaturatedcarbocyclic ring, an 8-10 membered bicyclic saturated, partiallyunsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur, a 4-7 membered saturated or partially unsaturated heterocyclicring having 1-3 heteroatoms independently selected from nitrogen,oxygen, or sulfur, a 7-10 membered bicyclic saturated or partiallyunsaturated heterocyclic ring having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclicheteroaryl ring having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; or (2) —X-E is hydrogen, halogen, —OR^(a),—O(CH₂)₁₋₄R^(a), —CN, —NO₂; R⁴ and R⁵ are each independently selectedfrom the group consisting of hydrogen, halogen, hydroxy, cyano, OCF₃,OCF₂H, C₁₋₆ alkyl, optionally substituted with one to five fluorines,C₃₋₆ cycloalkyl, optionally substituted with one to five fluorines,C₁₋₄alkoxy, optionally substituted with one to five fluorines, C₁₋₄alkylthio, optionally substituted with one to five fluorines, C₁₋₄alkylsulfonyl, optionally substituted with one to five fluorines,carboxy, C₁₋₄ alkyloxycarbonyl, and C₁₋₄ alkylcarbonyl; R^(a) and R^(b)are each independently hydrogen, fluorine, or C₁₋₃ alkyl, optionallysubstituted with one to five fluorines; R^(c) is hydrogen or C₁₋₃ alkyl,optionally substituted with one to five fluorines; R³ is a group havinga double bond, an isomer thereof, a tautomer thereof, a pharmaceuticalacceptable solvate thereof, or a pharmaceutical acceptable prodrugthereof.
 2. The compound of claim 1, E is selected from aryl,heteroaryl, carbocyclyl, heterocyclyl, any of which is optionallysubstituted with one to three R⁵ substituents.
 3. The compound of claim1, wherein R³ is selected from the group consisting of:

Y is C(═O), OC(═O), NHC(═O), S═O, S(═O)₂, or NHS(═O)₂; and R⁶, R⁷, R⁸are each independently hydrogen, halogen, CN, C₁₋₄ alkyl, C₁₋₆alkoxyalkyl, C₁₋₈ alkylaminoalkyl, or C₁₋₄ alkylphenyl; or R⁷ and R⁸taken together form a bond.
 4. The compound of claim 3, wherein R³ isselected from the group consisting of:

Y is C(═O), OC(═O), NHC(═O), S═O, S(═O)₂, or NHS(═O)₂; R⁶, R⁷, R⁸ areeach independently hydrogen, halogen, CN, C₁₋₄ alkyl, C₁₋₆ alkoxyalkyl,C₁₋₈ alkylaminoalkyl, or C₁₋₄ alkylphenyl; and R⁷ and R⁸ are optionallytaken together form a bond.
 5. The compound of claim 3, wherein R³ isselected from the group consisting of:


6. The compound of claim 1, wherein A is CH, B is N; C is CH; D is C—R¹;and R¹ is hydrogen, halogen, OH, CN, C₁₋₆alkyl, C₁₋₄alkoxy, C₁₋₆alkylsubstituted with one to five fluorines, C₁₋₄alkoxy substituted with oneto five fluorines, C₁₋₄alkoxy substituted with OH, C₁₋₄alkoxysubstituted with NH₂ or N(CH₃)₂, or


7. The compound of claim 6, wherein R¹ is hydrogen, Cl, F, OH, CN,—CHF₂, —CH₃, —OCH₃—OCH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH(CH₃)₂,—OCH₂CH₂OH, —OCH₂CH₂NH₂, —OCH₂CH₂N(CH₃)₂, or


8. A compound of claim 7 selected from the group consisting of


9. A pharmaceutical composition comprising a therapeutically effectiveamount of the compound of claim 1, and a pharmaceutically acceptableexcipient.
 10. A method for treating an autoimmune disease comprisingadministering to a subject in need thereof a composition containing atherapeutically effective amount of the compound of claim
 1. 11. Apharmaceutical composition for preventing or treating cancers, tumors,inflammatory diseases, autoimmune diseases, or immunologically mediateddisease comprising a therapeutically effective amount of the compound ofclaim 1, and a pharmaceutically acceptable excipient.
 12. A method fortreating an autoimmune disease, cancers, tumors, inflammatory diseases,or immunologically mediated diseases comprising administering to asubject in need thereof a composition containing a therapeuticallyeffective amount of the compound of claim 1 and other therapeuticagents.